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<blockquote data-quote="BadassBlues" data-source="post: 263291" data-attributes="member: 38526"><p>[URL unfurl="true"]https://en.wikipedia.org/wiki/Autophagy[/URL]</p><p></p><h3>Autophagy</h3><p></p><p></p><p>From Wikipedia, the free encyclopedia</p><p></p><p>Not to be confused with <a href="https://en.wikipedia.org/wiki/Autophagia" target="_blank">Autophagia</a>.</p><p>This article is about the cellular process. For other uses, see <a href="https://en.wikipedia.org/wiki/Autophagy_(disambiguation)" target="_blank">Autophagy (disambiguation)</a>.</p><p><a href="https://en.wikipedia.org/wiki/File:Autophagy_diagram_PLoS_Biology.jpg" target="_blank"><img src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f1/Autophagy_diagram_PLoS_Biology.jpg/220px-Autophagy_diagram_PLoS_Biology.jpg" class="bbImage" alt="" data-url="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f1/Autophagy_diagram_PLoS_Biology.jpg/220px-Autophagy_diagram_PLoS_Biology.jpg" style="" /></a><strong>A</strong> Diagram of the process of autophagy, which produces the structures <a href="https://en.wikipedia.org/wiki/Autophagosomes" target="_blank">autophagosomes</a> (AP), and <a href="https://en.wikipedia.org/wiki/Autolysosome" target="_blank">autolysosomes</a> (AL); <strong>B</strong> Electron micrograph of autophagic structures AP and AL in the <a href="https://en.wikipedia.org/wiki/Fat_body" target="_blank">fat body</a> of a <a href="https://en.wikipedia.org/wiki/Drosophila" target="_blank">fruit fly</a> larva; <strong>C</strong>Fluorescently-labeled autophagosomes AP in liver cells of starved mice.</p><p><strong>Autophagy</strong> (or <strong>autophagocytosis</strong>; from the <a href="https://en.wikipedia.org/wiki/Ancient_Greek" target="_blank">Ancient Greek</a> αὐτόφαγος, <em>autóphagos</em>, meaning "self-devouring"<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-1" target="_blank">[1]</a> and κύτος, <em>kýtos</em>, meaning "hollow")<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-2" target="_blank">[2]</a> is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky-3" target="_blank">[3]</a> It allows the orderly degradation and recycling of cellular components.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_review-4" target="_blank">[4]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Kobayashi2015-5" target="_blank">[5]</a> Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the <a href="https://en.wikipedia.org/wiki/Homeostasis" target="_blank">homeostasis</a> of non-starved cells.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:4-6" target="_blank">[6]</a> Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:4-6" target="_blank">[6]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-7" target="_blank">[7]</a></p><p>Four forms of autophagy have been identified: <a href="https://en.wikipedia.org/wiki/Macroautophagy" target="_blank">macroautophagy</a>, <a href="https://en.wikipedia.org/wiki/Microautophagy" target="_blank">microautophagy</a>, <a href="https://en.wikipedia.org/wiki/Chaperone-mediated_autophagy" target="_blank">chaperone-mediated autophagy</a> (CMA), and crinophagy.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid32620244-8" target="_blank">[8]</a> In macroautophagy (the most thoroughly researched form of autophagy), <a href="https://en.wikipedia.org/wiki/Cytoplasm" target="_blank">cytoplasmic</a> components (like mitochondria) are targeted and isolated from the rest of the cell within a double-membrane <a href="https://en.wikipedia.org/wiki/Vesicle_(biology_and_chemistry)" target="_blank">vesicle</a> known as an <a href="https://en.wikipedia.org/wiki/Autophagosome" target="_blank">autophagosome</a>,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_ARCDB_review-9" target="_blank">[9]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_2007_review-10" target="_blank">[10]</a> which, in time, fuses with an available <a href="https://en.wikipedia.org/wiki/Lysosome" target="_blank">lysosome</a>, bringing its specialty process of waste management and disposal; and eventually the contents of the vesicle (now called an <a href="https://en.wikipedia.org/wiki/Autolysosome" target="_blank">autolysosome</a>) are degraded and recycled. In crinophagy (the least well-known and researched form of autophagy), unnecessary <a href="https://en.wikipedia.org/wiki/Secretion" target="_blank">secretory granules</a> are degraded and recycled.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid32620244-8" target="_blank">[8]</a></p><p>In disease, autophagy has been seen as an adaptive response to stress, promoting survival of the cell; but in other cases, it appears to promote cell death and <a href="https://en.wikipedia.org/wiki/Morbidity" target="_blank">morbidity</a>. In the extreme case of starvation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels.</p><p>The word "autophagy" was in existence and frequently used from the middle of the 19th century.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-11" target="_blank">[11]</a> In its present usage, the term autophagy was coined by Belgian biochemist <a href="https://en.wikipedia.org/wiki/Christian_de_Duve" target="_blank">Christian de Duve</a> in 1963 based on his discovery of the functions of lysosome.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky-3" target="_blank">[3]</a> The identification of autophagy-related genes in yeast in the 1990s allowed researchers to deduce the mechanisms of autophagy,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1992-12" target="_blank">[12]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1992-13" target="_blank">[13]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-thumm_1994-14" target="_blank">[14]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1993-15" target="_blank">[15]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1995-16" target="_blank">[16]</a> which eventually led to the award of the 2016 <a href="https://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine" target="_blank">Nobel Prize in Physiology or Medicine</a> to Japanese researcher <a href="https://en.wikipedia.org/wiki/Yoshinori_Ohsumi" target="_blank">Yoshinori Ohsumi</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-nobelprize-17" target="_blank">[17]</a></p><h3>History[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=1" target="_blank">edit</a>]</h3><p>Autophagy was first observed by <a href="https://en.wikipedia.org/wiki/Keith_R._Porter" target="_blank">Keith R. Porter</a> and his student Thomas Ashford at the <a href="https://en.wikipedia.org/wiki/Rockefeller_University" target="_blank">Rockefeller Institute</a>. In January 1962 they reported an increased number of lysosomes in rat liver cells after the addition of <a href="https://en.wikipedia.org/wiki/Glucagon" target="_blank">glucagon</a>, and that some displaced lysosomes towards the centre of the cell contained other cell organelles such as <a href="https://en.wikipedia.org/wiki/Mitochondria" target="_blank">mitochondria</a>. They called this <a href="https://en.wikipedia.org/wiki/Autolysis_(biology)" target="_blank">autolysis</a> after <a href="https://en.wikipedia.org/wiki/Christian_de_Duve" target="_blank">Christian de Duve</a> and <a href="https://en.wikipedia.org/wiki/Alex_B._Novikoff" target="_blank">Alex B. Novikoff</a>. However Porter and Ashford wrongly interpreted their data as lysosome formation (ignoring the pre-existing organelles). Lysosomes could not be cell organelles, but part of <a href="https://en.wikipedia.org/wiki/Cytoplasm" target="_blank">cytoplasm</a> such as <a href="https://en.wikipedia.org/wiki/Mitochondria" target="_blank">mitochondria</a>, and that <a href="https://en.wikipedia.org/wiki/Hydrolytic_enzymes" target="_blank">hydrolytic enzymes</a> were produced by microbodies.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-18" target="_blank">[18]</a> In 1963 Hruban, Spargo and colleagues published a detailed ultrastructural description of "focal cytoplasmic degradation", which referenced a 1955 German study of injury-induced sequestration. Hruban, Spargo and colleagues recognized three continuous stages of maturation of the sequestered cytoplasm to lysosomes, and that the process was not limited to injury states that functioned under physiological conditions for "reutilization of cellular materials", and the "disposal of organelles" during differentiation.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-19" target="_blank">[19]</a> Inspired by this discovery, de Duve christened the phenomena "autophagy". Unlike Porter and Ashford, de Duve conceived the term as a part of lysosomal function while describing the role of glucagon as a major inducer of cell degradation in the liver. With his student Russell Deter, he established that lysosomes are responsible for glucagon-induced autophagy.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-20" target="_blank">[20]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-21" target="_blank">[21]</a> This was the first time the fact that lysosomes are the sites of intracellular autophagy was established.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky-3" target="_blank">[3]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-22" target="_blank">[22]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-23" target="_blank">[23]</a></p><p>In the 1990s several groups of scientists independently discovered autophagy-related genes using the <a href="https://en.wikipedia.org/wiki/Yeast" target="_blank">budding yeast</a>. Notably, <a href="https://en.wikipedia.org/wiki/Yoshinori_Ohsumi" target="_blank">Yoshinori Ohsumi</a> and Michael Thumm examined starvation-induced non-selective autophagy;<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1992-13" target="_blank">[13]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-thumm_1994-14" target="_blank">[14]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1993-15" target="_blank">[15]</a> in the meantime, <a href="https://en.wikipedia.org/wiki/Daniel_J._Klionsky" target="_blank">Daniel J. Klionsky</a> discovered the cytoplasm-to-vacuole targeting (CVT) pathway, which is a form of selective autophagy.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1992-12" target="_blank">[12]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1995-16" target="_blank">[16]</a> They soon found that they were in fact looking at essentially the same pathway, just from different angles.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionksy_1996_jbc-24" target="_blank">[24]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1996_pnas-25" target="_blank">[25]</a> Initially, the genes discovered by these and other yeast groups were given different names (APG, AUT, CVT, GSA, PAG, PAZ, and PDD). A unified nomenclature was advocated in 2003 by the yeast researchers to use ATG to denote autophagy genes.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_2003_dc-26" target="_blank">[26]</a> The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-nobelprize-17" target="_blank">[17]</a> although some have pointed out that the award could have been more inclusive.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-nature_news-27" target="_blank">[27]</a></p><p>The field of autophagy research experienced accelerated growth at the turn of the 21st century. Knowledge of ATG genes provided scientists more convenient tools to dissect functions of autophagy in human health and disease. In 1999, a landmark discovery connecting autophagy with cancer was published by Beth Levine's group.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-levine_1999-28" target="_blank">[28]</a> To this date, relationship between cancer and autophagy continues to be a main theme of autophagy research. The roles of autophagy in neurodegeneration and immune defense also received considerable attention. In 2003, the first Gordon Research Conference on autophagy was held at Waterville.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-gordon_2003-29" target="_blank">[29]</a> In 2005, Daniel J Klionsky launched <a href="https://en.wikipedia.org/wiki/Autophagy_(journal)" target="_blank"><em>Autophagy</em></a>, a scientific journal dedicated to this field. The first <a href="https://en.wikipedia.org/w/index.php?title=Keystone_Symposia_Conference&action=edit&redlink=1" target="_blank">Keystone Symposia Conference</a> on autophagy was held in 2007 at Monterey.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-keystone_2007-30" target="_blank">[30]</a> In 2008, Carol A Mercer created a BHMT fusion protein (GST-BHMT), which showed starvation-induced site-specific fragmentation in cell lines. The degradation of betaine homocysteine methyltransferase (BHMT), a metabolic enzyme, could be used to assess autophagy flux in mammalian cells. Macro, micro, and Chaperone mediated autophagy are mediated by autophagy-related genes and their associated enzymes.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_ARCDB_review-9" target="_blank">[9]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_2007_review-10" target="_blank">[10]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Lee12-31" target="_blank">[31]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32" target="_blank">[32]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-auto-33" target="_blank">[33]</a> Macroautophagy is then divided into bulk and selective autophagy. In the selective autophagy is the autophagy of organelles; mitophagy,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-34" target="_blank">[34]</a> lipophagy,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:1-35" target="_blank">[35]</a> pexophagy,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-36" target="_blank">[36]</a> chlorophagy,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-37" target="_blank">[37]</a> ribophagy<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-38" target="_blank">[38]</a> and others.</p><p><strong>Macroautophagy</strong> is the main pathway, used primarily to eradicate damaged cell <a href="https://en.wikipedia.org/wiki/Organelle" target="_blank">organelles</a> or unused <a href="https://en.wikipedia.org/wiki/Proteins" target="_blank">proteins</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Levine11-39" target="_blank">[39]</a> First the phagophore engulfs the material that needs to be degraded, which forms a double <a href="https://en.wikipedia.org/wiki/Biological_membrane" target="_blank">membrane</a> known as an <a href="https://en.wikipedia.org/wiki/Autophagosome" target="_blank">autophagosome</a>, around the organelle marked for destruction.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32" target="_blank">[32]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Pegan12-40" target="_blank">[40]</a> The <a href="https://en.wikipedia.org/wiki/Autophagosome" target="_blank">autophagosome</a> then travels through the cytoplasm of the cell to a lysosome in mammals, or vacuoles in yeast and plants,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-41" target="_blank">[41]</a> and the two organelles fuse.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32" target="_blank">[32]</a> Within the lysosome/vacuole, the contents of the autophagosome are degraded via acidic lysosomal hydrolase.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Homma2011-42" target="_blank">[42]</a></p><p><strong><a href="https://en.wikipedia.org/wiki/Microautophagy" target="_blank">Microautophagy</a></strong>, on the other hand, involves the direct engulfment of cytoplasmic material into the lysosome.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-43" target="_blank">[43]</a> This occurs by invagination, meaning the inward folding of the lysosomal membrane, or cellular protrusion.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Pegan12-40" target="_blank">[40]</a></p><p><strong><a href="https://en.wikipedia.org/wiki/Chaperone-mediated_autophagy" target="_blank">Chaperone-mediated autophagy</a></strong>, or CMA, is a very complex and specific pathway, which involves the recognition by the hsc70-containing complex.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Pegan12-40" target="_blank">[40]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Cuervo2008-44" target="_blank">[44]</a> This means that a protein must contain the recognition site for this <a href="https://en.wikipedia.org/wiki/Hsc70" target="_blank">hsc70</a> complex which will allow it to bind to this chaperone, forming the CMA- substrate/chaperone complex.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Homma2011-42" target="_blank">[42]</a> This complex then moves to the lysosomal membrane-bound protein that will recognise and bind with the CMA receptor. Upon recognition, the substrate protein gets unfolded and it is translocated across the lysosome membrane with the assistance of the lysosomal hsc70 chaperone.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Lee12-31" target="_blank">[31]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32" target="_blank">[32]</a> CMA is significantly different from other types of autophagy because it translocates protein material in a one by one manner, and it is extremely selective about what material crosses the lysosomal barrier.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Levine11-39" target="_blank">[39]</a></p><p><strong><a href="https://en.wikipedia.org/wiki/Mitophagy" target="_blank">Mitophagy</a></strong> is the selective degradation of <a href="https://en.wikipedia.org/wiki/Mitochondria" target="_blank">mitochondria</a> by autophagy. It often occurs to defective mitochondria following damage or stress. Mitophagy promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria which can lead to cellular degeneration. It is mediated by <a href="https://en.wikipedia.org/w/index.php?title=Atg32&action=edit&redlink=1" target="_blank">Atg32</a> (in yeast) and <a href="https://en.wikipedia.org/wiki/Nix_(gene)" target="_blank">NIX</a> and its regulator <a href="https://en.wikipedia.org/wiki/BNIP3" target="_blank">BNIP3</a> in mammals. Mitophagy is regulated by <a href="https://en.wikipedia.org/wiki/PINK1" target="_blank">PINK1</a> and <a href="https://en.wikipedia.org/wiki/Parkin_(ligase)" target="_blank">parkin</a> proteins. The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-auto-33" target="_blank">[33]</a></p><p><strong>Lipophagy</strong> is the degradation of lipids by autophagy,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:1-35" target="_blank">[35]</a> a function which has been shown to exist in both animal and fungal cells.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-45" target="_blank">[45]</a> The role of lipophagy in plant cells, however, remains elusive.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-46" target="_blank">[46]</a> In lipophagy the target are lipid structures called <a href="https://en.wikipedia.org/wiki/Lipid_droplet" target="_blank">lipid droplets</a> (LDs), spheric "organelles" with a core of mainly <a href="https://en.wikipedia.org/wiki/Triacylglycerols" target="_blank">triacylglycerols</a> (TAGs) and a unilayer of <a href="https://en.wikipedia.org/wiki/Phospholipid" target="_blank">phospholipids</a> and <a href="https://en.wikipedia.org/wiki/Membrane_protein" target="_blank">membrane proteins</a>. In animal cells the main lipophagic pathway is via the engulfment of LDs by the phagophore, macroautophagy. In fungal cells on the other hand microplipophagy constitutes the main pathway and is especially well studied in the budding yeast <em><a href="https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae" target="_blank">Saccharomyces cerevisiae</a></em><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-47" target="_blank">[47]</a><em>.</em> Lipophagy was first discovered in mice and published 2009.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-48" target="_blank">[48]</a></p><h3>Targeted interplay between bacterial pathogens and host autophagy[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=2" target="_blank">edit</a>]</h3><p>Autophagy targets genus-specific proteins, so orthologous proteins which share sequence homology with each other are recognized as substrates by a particular autophagy targeting protein. There exists a complementarity of autophagy targeting proteins which potentially increase infection risk upon mutation. The lack of overlap among the targets of the 3 autophagy proteins and the large overlap in terms of the genera show that autophagy could target different sets of bacterial proteins from a same pathogen. On one hand, the redundancy in targeting a same genera is beneficial for robust pathogen recognition. But, on the other hand, the complementarity in the specific bacterial proteins could make the host more susceptible to chronic disorders and infections if the gene encoding one of the autophagy targeting proteins becomes mutated, and the autophagy system is overloaded or suffers other malfunctions. Moreover, autophagy targets virulence factors and virulence factors responsible for more general functions such as nutrient acquisition and motility are recognized by multiple autophagy targeting proteins. And the specialized virulence factors such as autolysins, and iron sequestering proteins are potentially recognized uniquely by a single autophagy targeting protein. The autophagy proteins CALCOCO2/NDP52 and MAP1LC3/LC3 may have evolved specifically to target pathogens or pathogenic proteins for autophagic degradation. While SQSTM1/p62 targets more generic bacterial proteins containing a target motif but not related to virulence.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:5-49" target="_blank">[49]</a></p><p>On the other hand, bacterial proteins from various pathogenic genera are also able to modulate autophagy. There are genus-specific patterns in the phases of autophagy that are potentially regulated by a given pathogen group. Some autophagy phases can only be modulated by particular pathogens, while some phases are modulated by multiple pathogen genera. Some of the interplay-related bacterial proteins have proteolytic and post-translational activity such as phosphorylation and ubiquitination and can interfere with the activity of autophagy proteins.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:5-49" target="_blank">[49]</a></p><h3>Molecular biology[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=3" target="_blank">edit</a>]</h3><p>Autophagy is executed by autophagy-related (Atg) genes. Prior to 2003, ten or more names were used, but after this point a unified nomenclature was devised by fungal autophagy researchers.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:2-50" target="_blank">[50]</a> Atg or ATG stands for autophagy related. It does not specify gene or a protein.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:2-50" target="_blank">[50]</a></p><p>The first autophagy genes were identified by genetic screens conducted in <em>Saccharomyces cerevisiae</em>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1992-12" target="_blank">[12]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1992-13" target="_blank">[13]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-thumm_1994-14" target="_blank">[14]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1993-15" target="_blank">[15]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1995-16" target="_blank">[16]</a> Following their identification those genes were functionally characterized and their <a href="https://en.wikipedia.org/wiki/Ortholog" target="_blank">orthologs</a> in a variety of different organisms were identified and studied.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_ARCDB_review-9" target="_blank">[9]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-A._Lamb,_T._Yoshimori_2013-51" target="_blank">[51]</a> Today, thirty-six Atg proteins have been classified as especially important for autophagy, of which 18 belong to the core machinery<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-52" target="_blank">[52]</a></p><p>In mammals, <a href="https://en.wikipedia.org/wiki/Amino_acid" target="_blank">amino acid</a> sensing and additional signals such as <a href="https://en.wikipedia.org/wiki/Growth_factor" target="_blank">growth factors</a> and <a href="https://en.wikipedia.org/wiki/Reactive_oxygen_species" target="_blank">reactive oxygen species</a> regulate the activity of the protein <a href="https://en.wikipedia.org/wiki/Kinases" target="_blank">kinases</a> <a href="https://en.wikipedia.org/wiki/MTOR" target="_blank">mTOR</a> and <a href="https://en.wikipedia.org/wiki/AMPK" target="_blank">AMPK</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-A._Lamb,_T._Yoshimori_2013-51" target="_blank">[51]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-53" target="_blank">[53]</a> These two kinases regulate autophagy through inhibitory phosphorylation of the Unc-51-like kinases <a href="https://en.wikipedia.org/wiki/ULK1" target="_blank">ULK1</a> and ULK2 (mammalian homologues of Atg1).<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-54" target="_blank">[54]</a> Induction of autophagy results in the dephosphorylation and activation of the ULK kinases. ULK is part of a protein complex containing <a href="https://en.wikipedia.org/wiki/Autophagy-related_protein_13" target="_blank">Atg13</a>, <a href="https://en.wikipedia.org/wiki/Autophagy-related_protein_101" target="_blank">Atg101</a> and <a href="https://en.wikipedia.org/wiki/FIP200" target="_blank">FIP200</a>. ULK phosphorylates and activates <a href="https://en.wikipedia.org/wiki/Beclin-1" target="_blank">Beclin-1</a> (mammalian homologue of <a href="https://en.wikipedia.org/wiki/Atg6" target="_blank">Atg6</a>),<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Russell_2013-55" target="_blank">[55]</a> which is also part of a protein complex. The autophagy-inducible Beclin-1 complex<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Itakura_2008-56" target="_blank">[56]</a> contains the proteins <a href="https://en.wikipedia.org/wiki/PIK3R4" target="_blank">PIK3R4</a>(p150), <a href="https://en.wikipedia.org/w/index.php?title=Atg14L&action=edit&redlink=1" target="_blank">Atg14L</a> and the class III phosphatidylinositol 3-phosphate kinase (PI(3)K) <a href="https://en.wikipedia.org/wiki/Vps34" target="_blank">Vps34</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Kang_2011-57" target="_blank">[57]</a> The active ULK and Beclin-1 complexes re-localize to the site of autophagosome initiation, the phagophore, where they both contribute to the activation of downstream autophagy components.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Di_Bartolomeo_2010-58" target="_blank">[58]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Hara_2008-59" target="_blank">[59]</a></p><p>Once active, VPS34 phosphorylates the <a href="https://en.wikipedia.org/wiki/Lipid" target="_blank">lipid</a> <a href="https://en.wikipedia.org/wiki/Phosphatidylinositol" target="_blank">phosphatidylinositol</a> to generate phosphatidylinositol 3-phosphate (PtdIns(3)P) on the surface of the phagophore. The generated PtdIns(3)P is used as a docking point for proteins harboring a PtdIns(3)P binding motif. <a href="https://en.wikipedia.org/wiki/WIPI2" target="_blank">WIPI2</a>, a PtdIns(3)P binding protein of the WIPI (WD-repeat protein interacting with phosphoinositides) protein family, was recently shown to physically bind <a href="https://en.wikipedia.org/wiki/ATG16L1" target="_blank">ATG16L1</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-60" target="_blank">[60]</a> Atg16L1 is a member of an E3-like protein complex involved in one of two <a href="https://en.wikipedia.org/wiki/Ubiquitin" target="_blank">ubiquitin</a>-like conjugation systems essential for autophagosome formation. The FIP200 cis-Golgi-derived membranes fuse with ATG16L1-positive endosomal membranes to form the prophagophore termed HyPAS (hybrid pre-autophagosomal structure).<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:6-61" target="_blank">[61]</a> ATG16L1 binding to WIPI2<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid24954904-62" target="_blank">[62]</a> mediates ATG16L1's activity. This leads to downstream conversion of prophagophore into ATG8-positive phagophore<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:6-61" target="_blank">[61]</a> via a ubiquitin-like conjugation system.</p><p>The first of the two <a href="https://en.wikipedia.org/wiki/Ubiquitin-like_protein" target="_blank">ubiquitin-like</a> conjugation systems involved in autophagy <a href="https://en.wikipedia.org/wiki/Covalent" target="_blank">covalently</a> binds the ubiquitin-like protein <a href="https://en.wikipedia.org/wiki/ATG12" target="_blank">Atg12</a> to <a href="https://en.wikipedia.org/wiki/ATG5" target="_blank">Atg5</a>. The resulting conjugate protein then binds <a href="https://en.wikipedia.org/wiki/ATG16L1" target="_blank">ATG16L1</a> to form an E3-like complex which functions as part of the second ubiquitin-like conjugation system.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid17986448-63" target="_blank">[63]</a> This complex binds and activates <a href="https://en.wikipedia.org/wiki/Atg3" target="_blank">Atg3</a>, which covalently attaches mammalian homologues of the ubiquitin-like yeast protein <a href="https://en.wikipedia.org/wiki/ATG8" target="_blank">ATG8</a> (<a href="https://en.wikipedia.org/wiki/MAP1LC3A" target="_blank">LC3A-C</a>, GATE16, and GABARAPL1-3), the most studied being LC3 proteins, to the lipid <a href="https://en.wikipedia.org/wiki/Phosphatidylethanolamine" target="_blank">phosphatidylethanolamine</a> (PE) on the surface of autophagosomes.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid15169837-64" target="_blank">[64]</a> Lipidated LC3 contributes to the closure of autophagosomes,<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid18768752-65" target="_blank">[65]</a> and enables the docking of specific cargos and adaptor proteins such as Sequestosome-1/<a href="https://en.wikipedia.org/wiki/Sequestosome_1" target="_blank">p62</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid25483962-66" target="_blank">[66]</a> The completed autophagosome then fuses with a <a href="https://en.wikipedia.org/wiki/Lysosome" target="_blank">lysosome</a> through the actions of multiple proteins, including SNAREs<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid19781582-67" target="_blank">[67]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid20089838-68" target="_blank">[68]</a> and <a href="https://en.wikipedia.org/wiki/UVRAG" target="_blank">UVRAG</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid25533187-69" target="_blank">[69]</a> Following the fusion LC3 is retained on the vesicle's inner side and degraded along with the cargo, while the LC3 molecules attached to the outer side are cleaved off by <a href="https://en.wikipedia.org/w/index.php?title=Atg4&action=edit&redlink=1" target="_blank">Atg4</a> and recycled.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid19322194-70" target="_blank">[70]</a> The contents of the autolysosome are subsequently degraded and their building blocks are released from the vesicle through the action of <a href="https://en.wikipedia.org/wiki/Permease" target="_blank">permeases</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid17021250-71" target="_blank">[71]</a></p><p><a href="https://en.wikipedia.org/wiki/Sirtuin_1" target="_blank">Sirtuin 1</a> (SIRT1) stimulates autophagy by preventing <a href="https://en.wikipedia.org/wiki/Acetylation" target="_blank">acetylation</a> of proteins (via deacetylation) required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid32397145-72" target="_blank">[72]</a> This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-73" target="_blank">[73]</a></p><h3>Functions[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=4" target="_blank">edit</a>]</h3><h4>Nutrient starvation[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=5" target="_blank">edit</a>]</h4><p>Autophagy has roles in various cellular functions. One particular example is in yeasts, where the nutrient starvation induces a high level of autophagy. This allows unneeded proteins to be degraded and the amino acids recycled for the synthesis of proteins that are essential for survival.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Klionsky2002-74" target="_blank">[74]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-75" target="_blank">[75]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-76" target="_blank">[76]</a> In higher eukaryotes, autophagy is induced in response to the nutrient depletion that occurs in animals at birth after severing off the trans-placental food supply, as well as that of nutrient starved cultured cells and tissues.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Kuma2004-77" target="_blank">[77]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Ohsumi2004-78" target="_blank">[78]</a> Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Tsukada93-79" target="_blank">[79]</a> Studies on the <em>apg</em> mutants suggest that autophagy via autophagic bodies is indispensable for protein degradation in the vacuoles under starvation conditions, and that at least 15 APG genes are involved in autophagy in yeast.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Tsukada93-79" target="_blank">[79]</a> A gene known as ATG7 has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in <em>atg7</em>-deficient mice.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Ohsumi2004-78" target="_blank">[78]</a></p><h4>Infection[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=6" target="_blank">edit</a>]</h4><p><a href="https://en.wikipedia.org/wiki/Vesicular_stomatitis_virus" target="_blank">Vesicular stomatitis virus</a> is believed to be taken up by the autophagosome from the cytosol and translocated to the <a href="https://en.wikipedia.org/wiki/Endosome" target="_blank">endosomes</a> where detection takes place by a <a href="https://en.wikipedia.org/wiki/Pattern_recognition_receptor" target="_blank">pattern recognition receptor</a> called <a href="https://en.wikipedia.org/wiki/Toll-like_receptor_7" target="_blank">toll-like receptor 7</a>, detecting single stranded <a href="https://en.wikipedia.org/wiki/RNA" target="_blank">RNA</a>. Following activation of the toll-like receptor, intracellular signaling cascades are initiated, leading to induction of <a href="https://en.wikipedia.org/wiki/Interferon" target="_blank">interferon</a> and other antiviral <a href="https://en.wikipedia.org/wiki/Cytokine" target="_blank">cytokines</a>. A subset of viruses and bacteria subvert the autophagic pathway to promote their own replication.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-80" target="_blank">[80]</a> <a href="https://en.wikipedia.org/wiki/Galectin-8" target="_blank">Galectin-8</a> has recently been identified as an intracellular "danger receptor", able to initiate autophagy against intracellular pathogens. When galectin-8 binds to a damaged <a href="https://en.wikipedia.org/wiki/Vacuole" target="_blank">vacuole</a>, it recruits an autophagy adaptor such as <a href="https://en.wikipedia.org/wiki/CALCOCO2" target="_blank">NDP52</a> leading to the formation of an autophagosome and bacterial degradation.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-:3-81" target="_blank">[81]</a></p><h4>Repair mechanism[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=7" target="_blank">edit</a>]</h4><p>Autophagy degrades damaged organelles, cell membranes and proteins, and insufficient autophagy is thought to be one of the main reasons for the accumulation of damaged cells and <a href="https://en.wikipedia.org/wiki/Aging" target="_blank">aging</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Cuervo2005-82" target="_blank">[82]</a> Autophagy and autophagy regulators are involved in response to lysosomal damage, often directed by <a href="https://en.wikipedia.org/wiki/Galectin" target="_blank">galectins</a> such as <a href="https://en.wikipedia.org/wiki/Galectin-3" target="_blank">galectin-3</a> and <a href="https://en.wikipedia.org/wiki/Galectin-8" target="_blank">galectin-8</a>.</p><h4>Programmed cell death[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=8" target="_blank">edit</a>]</h4><p>One of the mechanisms of <a href="https://en.wikipedia.org/wiki/Programmed_cell_death" target="_blank">programmed cell death</a> (PCD) is associated with the appearance of autophagosomes and depends on autophagy proteins. This form of cell death most likely corresponds to a process that has been morphologically defined as autophagic PCD. One question that constantly arises, however, is whether autophagic activity in dying cells is the cause of death or is actually an attempt to prevent it. Morphological and histochemical studies have not so far proved a causative relationship between the autophagic process and cell death. In fact, there have recently been strong arguments that autophagic activity in dying cells might actually be a survival mechanism.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-tavassoly-83" target="_blank">[83]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Shimizu2005-84" target="_blank">[84]</a> Studies of the metamorphosis of insects have shown cells undergoing a form of PCD that appears distinct from other forms; these have been proposed as examples of autophagic cell death.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Osborne1993-85" target="_blank">[85]</a> Recent pharmacological and biochemical studies have proposed that survival and lethal autophagy can be distinguished by the type and degree of regulatory signaling during stress particularly after viral infection.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Datan-86" target="_blank">[86]</a> Although promising, these findings have not been examined in non-viral systems.</p><h3>Exercise[<a href="https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit&section=9" target="_blank">edit</a>]</h3><p>Autophagy is essential for basal <a href="https://en.wikipedia.org/wiki/Homeostasis" target="_blank">homeostasis</a>; it is also extremely important in maintaining <a href="https://en.wikipedia.org/wiki/Muscle" target="_blank">muscle</a> homeostasis during physical exercise.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pimd111111-87" target="_blank">[87]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Klionsky2011-88" target="_blank">[88]</a> Autophagy at the molecular level is only partially understood. A study of mice shows that autophagy is important for the ever-changing demands of their nutritional and energy needs, particularly through the metabolic pathways of protein catabolism. In a 2012 study conducted by the <a href="https://en.wikipedia.org/wiki/University_of_Texas_Southwestern_Medical_Center" target="_blank">University of Texas Southwestern Medical Center</a> in <a href="https://en.wikipedia.org/wiki/Dallas" target="_blank">Dallas</a>, mutant <a href="https://en.wikipedia.org/wiki/Mouse" target="_blank">mice</a> (with a knock-in mutation of <a href="https://en.wikipedia.org/wiki/BCL2" target="_blank">BCL2</a> phosphorylation sites to produce progeny that showed normal levels of basal autophagy yet were deficient in stress-induced autophagy) were tested to challenge this theory. Results showed that when compared to a control group, these mice illustrated a decrease in endurance and an altered <a href="https://en.wikipedia.org/wiki/Glucose" target="_blank">glucose</a> metabolism during acute exercise.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-He2012-89" target="_blank">[89]</a></p><p>Another study demonstrated that <a href="https://en.wikipedia.org/wiki/Skeletal_muscle" target="_blank">skeletal muscle</a> fibers of <a href="https://en.wikipedia.org/wiki/Collagen_VI" target="_blank">collagen VI</a> in <a href="https://en.wikipedia.org/wiki/Knockout_mice" target="_blank">knockout mice</a> showed signs of degeneration due to an insufficiency of autophagy which led to an accumulation of damaged mitochondria and excessive <a href="https://en.wikipedia.org/wiki/Apoptosis" target="_blank">cell death</a>.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Grumati11-90" target="_blank">[90]</a> Exercise-induced autophagy was unsuccessful however; but when autophagy was induced artificially post-exercise, the accumulation of damaged organelles in <a href="https://en.wikipedia.org/wiki/Collagen_VI" target="_blank">collagen VI</a> deficient muscle fibres was prevented and cellular homeostasis was maintained. Both studies demonstrate that autophagy induction may contribute to the beneficial metabolic effects of exercise and that it is essential in the maintaining of muscle homeostasis during exercise, particularly in collagen VI fibers.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-He2012-89" target="_blank">[89]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Klionsky2011-88" target="_blank">[88]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-Grumati11-90" target="_blank">[90]</a></p><p>Work at the Institute for Cell Biology, University of Bonn, showed that a certain type of autophagy, i.e. <a href="https://en.wikipedia.org/wiki/Chaperone-assisted_selective_autophagy_(CASA)" target="_blank">chaperone-assisted selective autophagy (CASA)</a>, is induced in contracting muscles and is required for maintaining the muscle <a href="https://en.wikipedia.org/wiki/Sarcomere" target="_blank">sarcomere</a> under mechanical tension.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid20060297-91" target="_blank">[91]</a> The CASA chaperone complex recognizes mechanically damaged cytoskeleton components and directs these components through a <a href="https://en.wikipedia.org/wiki/Ubiquitin" target="_blank">ubiquitin</a>-dependent autophagic sorting pathway to lysosomes for disposal. This is necessary for maintaining muscle activity.<a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid20060297-91" target="_blank">[91]</a><a href="https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid23434281-92" target="_blank">[92]</a></p><h3></h3></blockquote><p></p>
[QUOTE="BadassBlues, post: 263291, member: 38526"] [URL unfurl="true"]https://en.wikipedia.org/wiki/Autophagy[/URL] [HEADING=2]Autophagy[/HEADING] From Wikipedia, the free encyclopedia Not to be confused with [URL='https://en.wikipedia.org/wiki/Autophagia']Autophagia[/URL]. This article is about the cellular process. For other uses, see [URL='https://en.wikipedia.org/wiki/Autophagy_(disambiguation)']Autophagy (disambiguation)[/URL]. [URL='https://en.wikipedia.org/wiki/File:Autophagy_diagram_PLoS_Biology.jpg'][IMG]https://upload.wikimedia.org/wikipedia/commons/thumb/f/f1/Autophagy_diagram_PLoS_Biology.jpg/220px-Autophagy_diagram_PLoS_Biology.jpg[/IMG][/URL][B]A[/B] Diagram of the process of autophagy, which produces the structures [URL='https://en.wikipedia.org/wiki/Autophagosomes']autophagosomes[/URL] (AP), and [URL='https://en.wikipedia.org/wiki/Autolysosome']autolysosomes[/URL] (AL); [B]B[/B] Electron micrograph of autophagic structures AP and AL in the [URL='https://en.wikipedia.org/wiki/Fat_body']fat body[/URL] of a [URL='https://en.wikipedia.org/wiki/Drosophila']fruit fly[/URL] larva; [B]C[/B]Fluorescently-labeled autophagosomes AP in liver cells of starved mice. [B]Autophagy[/B] (or [B]autophagocytosis[/B]; from the [URL='https://en.wikipedia.org/wiki/Ancient_Greek']Ancient Greek[/URL] αὐτόφαγος, [I]autóphagos[/I], meaning "self-devouring"[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-1'][1][/URL] and κύτος, [I]kýtos[/I], meaning "hollow")[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-2'][2][/URL] is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky-3'][3][/URL] It allows the orderly degradation and recycling of cellular components.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_review-4'][4][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Kobayashi2015-5'][5][/URL] Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the [URL='https://en.wikipedia.org/wiki/Homeostasis']homeostasis[/URL] of non-starved cells.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:4-6'][6][/URL] Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:4-6'][6][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-7'][7][/URL] Four forms of autophagy have been identified: [URL='https://en.wikipedia.org/wiki/Macroautophagy']macroautophagy[/URL], [URL='https://en.wikipedia.org/wiki/Microautophagy']microautophagy[/URL], [URL='https://en.wikipedia.org/wiki/Chaperone-mediated_autophagy']chaperone-mediated autophagy[/URL] (CMA), and crinophagy.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid32620244-8'][8][/URL] In macroautophagy (the most thoroughly researched form of autophagy), [URL='https://en.wikipedia.org/wiki/Cytoplasm']cytoplasmic[/URL] components (like mitochondria) are targeted and isolated from the rest of the cell within a double-membrane [URL='https://en.wikipedia.org/wiki/Vesicle_(biology_and_chemistry)']vesicle[/URL] known as an [URL='https://en.wikipedia.org/wiki/Autophagosome']autophagosome[/URL],[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_ARCDB_review-9'][9][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_2007_review-10'][10][/URL] which, in time, fuses with an available [URL='https://en.wikipedia.org/wiki/Lysosome']lysosome[/URL], bringing its specialty process of waste management and disposal; and eventually the contents of the vesicle (now called an [URL='https://en.wikipedia.org/wiki/Autolysosome']autolysosome[/URL]) are degraded and recycled. In crinophagy (the least well-known and researched form of autophagy), unnecessary [URL='https://en.wikipedia.org/wiki/Secretion']secretory granules[/URL] are degraded and recycled.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid32620244-8'][8][/URL] In disease, autophagy has been seen as an adaptive response to stress, promoting survival of the cell; but in other cases, it appears to promote cell death and [URL='https://en.wikipedia.org/wiki/Morbidity']morbidity[/URL]. In the extreme case of starvation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels. The word "autophagy" was in existence and frequently used from the middle of the 19th century.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-11'][11][/URL] In its present usage, the term autophagy was coined by Belgian biochemist [URL='https://en.wikipedia.org/wiki/Christian_de_Duve']Christian de Duve[/URL] in 1963 based on his discovery of the functions of lysosome.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky-3'][3][/URL] The identification of autophagy-related genes in yeast in the 1990s allowed researchers to deduce the mechanisms of autophagy,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1992-12'][12][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1992-13'][13][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-thumm_1994-14'][14][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1993-15'][15][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1995-16'][16][/URL] which eventually led to the award of the 2016 [URL='https://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine']Nobel Prize in Physiology or Medicine[/URL] to Japanese researcher [URL='https://en.wikipedia.org/wiki/Yoshinori_Ohsumi']Yoshinori Ohsumi[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-nobelprize-17'][17][/URL] [HEADING=2]History[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=1']edit[/URL]][/HEADING] Autophagy was first observed by [URL='https://en.wikipedia.org/wiki/Keith_R._Porter']Keith R. Porter[/URL] and his student Thomas Ashford at the [URL='https://en.wikipedia.org/wiki/Rockefeller_University']Rockefeller Institute[/URL]. In January 1962 they reported an increased number of lysosomes in rat liver cells after the addition of [URL='https://en.wikipedia.org/wiki/Glucagon']glucagon[/URL], and that some displaced lysosomes towards the centre of the cell contained other cell organelles such as [URL='https://en.wikipedia.org/wiki/Mitochondria']mitochondria[/URL]. They called this [URL='https://en.wikipedia.org/wiki/Autolysis_(biology)']autolysis[/URL] after [URL='https://en.wikipedia.org/wiki/Christian_de_Duve']Christian de Duve[/URL] and [URL='https://en.wikipedia.org/wiki/Alex_B._Novikoff']Alex B. Novikoff[/URL]. However Porter and Ashford wrongly interpreted their data as lysosome formation (ignoring the pre-existing organelles). Lysosomes could not be cell organelles, but part of [URL='https://en.wikipedia.org/wiki/Cytoplasm']cytoplasm[/URL] such as [URL='https://en.wikipedia.org/wiki/Mitochondria']mitochondria[/URL], and that [URL='https://en.wikipedia.org/wiki/Hydrolytic_enzymes']hydrolytic enzymes[/URL] were produced by microbodies.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-18'][18][/URL] In 1963 Hruban, Spargo and colleagues published a detailed ultrastructural description of "focal cytoplasmic degradation", which referenced a 1955 German study of injury-induced sequestration. Hruban, Spargo and colleagues recognized three continuous stages of maturation of the sequestered cytoplasm to lysosomes, and that the process was not limited to injury states that functioned under physiological conditions for "reutilization of cellular materials", and the "disposal of organelles" during differentiation.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-19'][19][/URL] Inspired by this discovery, de Duve christened the phenomena "autophagy". Unlike Porter and Ashford, de Duve conceived the term as a part of lysosomal function while describing the role of glucagon as a major inducer of cell degradation in the liver. With his student Russell Deter, he established that lysosomes are responsible for glucagon-induced autophagy.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-20'][20][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-21'][21][/URL] This was the first time the fact that lysosomes are the sites of intracellular autophagy was established.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky-3'][3][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-22'][22][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-23'][23][/URL] In the 1990s several groups of scientists independently discovered autophagy-related genes using the [URL='https://en.wikipedia.org/wiki/Yeast']budding yeast[/URL]. Notably, [URL='https://en.wikipedia.org/wiki/Yoshinori_Ohsumi']Yoshinori Ohsumi[/URL] and Michael Thumm examined starvation-induced non-selective autophagy;[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1992-13'][13][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-thumm_1994-14'][14][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1993-15'][15][/URL] in the meantime, [URL='https://en.wikipedia.org/wiki/Daniel_J._Klionsky']Daniel J. Klionsky[/URL] discovered the cytoplasm-to-vacuole targeting (CVT) pathway, which is a form of selective autophagy.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1992-12'][12][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1995-16'][16][/URL] They soon found that they were in fact looking at essentially the same pathway, just from different angles.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionksy_1996_jbc-24'][24][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1996_pnas-25'][25][/URL] Initially, the genes discovered by these and other yeast groups were given different names (APG, AUT, CVT, GSA, PAG, PAZ, and PDD). A unified nomenclature was advocated in 2003 by the yeast researchers to use ATG to denote autophagy genes.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_2003_dc-26'][26][/URL] The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-nobelprize-17'][17][/URL] although some have pointed out that the award could have been more inclusive.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-nature_news-27'][27][/URL] The field of autophagy research experienced accelerated growth at the turn of the 21st century. Knowledge of ATG genes provided scientists more convenient tools to dissect functions of autophagy in human health and disease. In 1999, a landmark discovery connecting autophagy with cancer was published by Beth Levine's group.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-levine_1999-28'][28][/URL] To this date, relationship between cancer and autophagy continues to be a main theme of autophagy research. The roles of autophagy in neurodegeneration and immune defense also received considerable attention. In 2003, the first Gordon Research Conference on autophagy was held at Waterville.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-gordon_2003-29'][29][/URL] In 2005, Daniel J Klionsky launched [URL='https://en.wikipedia.org/wiki/Autophagy_(journal)'][I]Autophagy[/I][/URL], a scientific journal dedicated to this field. The first [URL='https://en.wikipedia.org/w/index.php?title=Keystone_Symposia_Conference&action=edit&redlink=1']Keystone Symposia Conference[/URL] on autophagy was held in 2007 at Monterey.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-keystone_2007-30'][30][/URL] In 2008, Carol A Mercer created a BHMT fusion protein (GST-BHMT), which showed starvation-induced site-specific fragmentation in cell lines. The degradation of betaine homocysteine methyltransferase (BHMT), a metabolic enzyme, could be used to assess autophagy flux in mammalian cells. Macro, micro, and Chaperone mediated autophagy are mediated by autophagy-related genes and their associated enzymes.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_ARCDB_review-9'][9][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_2007_review-10'][10][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Lee12-31'][31][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32'][32][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-auto-33'][33][/URL] Macroautophagy is then divided into bulk and selective autophagy. In the selective autophagy is the autophagy of organelles; mitophagy,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-34'][34][/URL] lipophagy,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:1-35'][35][/URL] pexophagy,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-36'][36][/URL] chlorophagy,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-37'][37][/URL] ribophagy[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-38'][38][/URL] and others. [B]Macroautophagy[/B] is the main pathway, used primarily to eradicate damaged cell [URL='https://en.wikipedia.org/wiki/Organelle']organelles[/URL] or unused [URL='https://en.wikipedia.org/wiki/Proteins']proteins[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Levine11-39'][39][/URL] First the phagophore engulfs the material that needs to be degraded, which forms a double [URL='https://en.wikipedia.org/wiki/Biological_membrane']membrane[/URL] known as an [URL='https://en.wikipedia.org/wiki/Autophagosome']autophagosome[/URL], around the organelle marked for destruction.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32'][32][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Pegan12-40'][40][/URL] The [URL='https://en.wikipedia.org/wiki/Autophagosome']autophagosome[/URL] then travels through the cytoplasm of the cell to a lysosome in mammals, or vacuoles in yeast and plants,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-41'][41][/URL] and the two organelles fuse.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32'][32][/URL] Within the lysosome/vacuole, the contents of the autophagosome are degraded via acidic lysosomal hydrolase.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Homma2011-42'][42][/URL] [B][URL='https://en.wikipedia.org/wiki/Microautophagy']Microautophagy[/URL][/B], on the other hand, involves the direct engulfment of cytoplasmic material into the lysosome.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-43'][43][/URL] This occurs by invagination, meaning the inward folding of the lysosomal membrane, or cellular protrusion.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Pegan12-40'][40][/URL] [B][URL='https://en.wikipedia.org/wiki/Chaperone-mediated_autophagy']Chaperone-mediated autophagy[/URL][/B], or CMA, is a very complex and specific pathway, which involves the recognition by the hsc70-containing complex.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Pegan12-40'][40][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Cuervo2008-44'][44][/URL] This means that a protein must contain the recognition site for this [URL='https://en.wikipedia.org/wiki/Hsc70']hsc70[/URL] complex which will allow it to bind to this chaperone, forming the CMA- substrate/chaperone complex.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Homma2011-42'][42][/URL] This complex then moves to the lysosomal membrane-bound protein that will recognise and bind with the CMA receptor. Upon recognition, the substrate protein gets unfolded and it is translocated across the lysosome membrane with the assistance of the lysosomal hsc70 chaperone.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Lee12-31'][31][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Yoshimori2002-32'][32][/URL] CMA is significantly different from other types of autophagy because it translocates protein material in a one by one manner, and it is extremely selective about what material crosses the lysosomal barrier.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Levine11-39'][39][/URL] [B][URL='https://en.wikipedia.org/wiki/Mitophagy']Mitophagy[/URL][/B] is the selective degradation of [URL='https://en.wikipedia.org/wiki/Mitochondria']mitochondria[/URL] by autophagy. It often occurs to defective mitochondria following damage or stress. Mitophagy promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria which can lead to cellular degeneration. It is mediated by [URL='https://en.wikipedia.org/w/index.php?title=Atg32&action=edit&redlink=1']Atg32[/URL] (in yeast) and [URL='https://en.wikipedia.org/wiki/Nix_(gene)']NIX[/URL] and its regulator [URL='https://en.wikipedia.org/wiki/BNIP3']BNIP3[/URL] in mammals. Mitophagy is regulated by [URL='https://en.wikipedia.org/wiki/PINK1']PINK1[/URL] and [URL='https://en.wikipedia.org/wiki/Parkin_(ligase)']parkin[/URL] proteins. The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-auto-33'][33][/URL] [B]Lipophagy[/B] is the degradation of lipids by autophagy,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:1-35'][35][/URL] a function which has been shown to exist in both animal and fungal cells.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-45'][45][/URL] The role of lipophagy in plant cells, however, remains elusive.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-46'][46][/URL] In lipophagy the target are lipid structures called [URL='https://en.wikipedia.org/wiki/Lipid_droplet']lipid droplets[/URL] (LDs), spheric "organelles" with a core of mainly [URL='https://en.wikipedia.org/wiki/Triacylglycerols']triacylglycerols[/URL] (TAGs) and a unilayer of [URL='https://en.wikipedia.org/wiki/Phospholipid']phospholipids[/URL] and [URL='https://en.wikipedia.org/wiki/Membrane_protein']membrane proteins[/URL]. In animal cells the main lipophagic pathway is via the engulfment of LDs by the phagophore, macroautophagy. In fungal cells on the other hand microplipophagy constitutes the main pathway and is especially well studied in the budding yeast [I][URL='https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae']Saccharomyces cerevisiae[/URL][/I][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-47'][47][/URL][I].[/I] Lipophagy was first discovered in mice and published 2009.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-48'][48][/URL] [HEADING=2]Targeted interplay between bacterial pathogens and host autophagy[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=2']edit[/URL]][/HEADING] Autophagy targets genus-specific proteins, so orthologous proteins which share sequence homology with each other are recognized as substrates by a particular autophagy targeting protein. There exists a complementarity of autophagy targeting proteins which potentially increase infection risk upon mutation. The lack of overlap among the targets of the 3 autophagy proteins and the large overlap in terms of the genera show that autophagy could target different sets of bacterial proteins from a same pathogen. On one hand, the redundancy in targeting a same genera is beneficial for robust pathogen recognition. But, on the other hand, the complementarity in the specific bacterial proteins could make the host more susceptible to chronic disorders and infections if the gene encoding one of the autophagy targeting proteins becomes mutated, and the autophagy system is overloaded or suffers other malfunctions. Moreover, autophagy targets virulence factors and virulence factors responsible for more general functions such as nutrient acquisition and motility are recognized by multiple autophagy targeting proteins. And the specialized virulence factors such as autolysins, and iron sequestering proteins are potentially recognized uniquely by a single autophagy targeting protein. The autophagy proteins CALCOCO2/NDP52 and MAP1LC3/LC3 may have evolved specifically to target pathogens or pathogenic proteins for autophagic degradation. While SQSTM1/p62 targets more generic bacterial proteins containing a target motif but not related to virulence.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:5-49'][49][/URL] On the other hand, bacterial proteins from various pathogenic genera are also able to modulate autophagy. There are genus-specific patterns in the phases of autophagy that are potentially regulated by a given pathogen group. Some autophagy phases can only be modulated by particular pathogens, while some phases are modulated by multiple pathogen genera. Some of the interplay-related bacterial proteins have proteolytic and post-translational activity such as phosphorylation and ubiquitination and can interfere with the activity of autophagy proteins.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:5-49'][49][/URL] [HEADING=2]Molecular biology[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=3']edit[/URL]][/HEADING] Autophagy is executed by autophagy-related (Atg) genes. Prior to 2003, ten or more names were used, but after this point a unified nomenclature was devised by fungal autophagy researchers.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:2-50'][50][/URL] Atg or ATG stands for autophagy related. It does not specify gene or a protein.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:2-50'][50][/URL] The first autophagy genes were identified by genetic screens conducted in [I]Saccharomyces cerevisiae[/I].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1992-12'][12][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1992-13'][13][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-thumm_1994-14'][14][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-ohsumi_1993-15'][15][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-klionsky_1995-16'][16][/URL] Following their identification those genes were functionally characterized and their [URL='https://en.wikipedia.org/wiki/Ortholog']orthologs[/URL] in a variety of different organisms were identified and studied.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-mizushima_2011_ARCDB_review-9'][9][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-A._Lamb,_T._Yoshimori_2013-51'][51][/URL] Today, thirty-six Atg proteins have been classified as especially important for autophagy, of which 18 belong to the core machinery[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-52'][52][/URL] In mammals, [URL='https://en.wikipedia.org/wiki/Amino_acid']amino acid[/URL] sensing and additional signals such as [URL='https://en.wikipedia.org/wiki/Growth_factor']growth factors[/URL] and [URL='https://en.wikipedia.org/wiki/Reactive_oxygen_species']reactive oxygen species[/URL] regulate the activity of the protein [URL='https://en.wikipedia.org/wiki/Kinases']kinases[/URL] [URL='https://en.wikipedia.org/wiki/MTOR']mTOR[/URL] and [URL='https://en.wikipedia.org/wiki/AMPK']AMPK[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-A._Lamb,_T._Yoshimori_2013-51'][51][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-53'][53][/URL] These two kinases regulate autophagy through inhibitory phosphorylation of the Unc-51-like kinases [URL='https://en.wikipedia.org/wiki/ULK1']ULK1[/URL] and ULK2 (mammalian homologues of Atg1).[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-54'][54][/URL] Induction of autophagy results in the dephosphorylation and activation of the ULK kinases. ULK is part of a protein complex containing [URL='https://en.wikipedia.org/wiki/Autophagy-related_protein_13']Atg13[/URL], [URL='https://en.wikipedia.org/wiki/Autophagy-related_protein_101']Atg101[/URL] and [URL='https://en.wikipedia.org/wiki/FIP200']FIP200[/URL]. ULK phosphorylates and activates [URL='https://en.wikipedia.org/wiki/Beclin-1']Beclin-1[/URL] (mammalian homologue of [URL='https://en.wikipedia.org/wiki/Atg6']Atg6[/URL]),[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Russell_2013-55'][55][/URL] which is also part of a protein complex. The autophagy-inducible Beclin-1 complex[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Itakura_2008-56'][56][/URL] contains the proteins [URL='https://en.wikipedia.org/wiki/PIK3R4']PIK3R4[/URL](p150), [URL='https://en.wikipedia.org/w/index.php?title=Atg14L&action=edit&redlink=1']Atg14L[/URL] and the class III phosphatidylinositol 3-phosphate kinase (PI(3)K) [URL='https://en.wikipedia.org/wiki/Vps34']Vps34[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Kang_2011-57'][57][/URL] The active ULK and Beclin-1 complexes re-localize to the site of autophagosome initiation, the phagophore, where they both contribute to the activation of downstream autophagy components.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Di_Bartolomeo_2010-58'][58][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Hara_2008-59'][59][/URL] Once active, VPS34 phosphorylates the [URL='https://en.wikipedia.org/wiki/Lipid']lipid[/URL] [URL='https://en.wikipedia.org/wiki/Phosphatidylinositol']phosphatidylinositol[/URL] to generate phosphatidylinositol 3-phosphate (PtdIns(3)P) on the surface of the phagophore. The generated PtdIns(3)P is used as a docking point for proteins harboring a PtdIns(3)P binding motif. [URL='https://en.wikipedia.org/wiki/WIPI2']WIPI2[/URL], a PtdIns(3)P binding protein of the WIPI (WD-repeat protein interacting with phosphoinositides) protein family, was recently shown to physically bind [URL='https://en.wikipedia.org/wiki/ATG16L1']ATG16L1[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-60'][60][/URL] Atg16L1 is a member of an E3-like protein complex involved in one of two [URL='https://en.wikipedia.org/wiki/Ubiquitin']ubiquitin[/URL]-like conjugation systems essential for autophagosome formation. The FIP200 cis-Golgi-derived membranes fuse with ATG16L1-positive endosomal membranes to form the prophagophore termed HyPAS (hybrid pre-autophagosomal structure).[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:6-61'][61][/URL] ATG16L1 binding to WIPI2[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid24954904-62'][62][/URL] mediates ATG16L1's activity. This leads to downstream conversion of prophagophore into ATG8-positive phagophore[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:6-61'][61][/URL] via a ubiquitin-like conjugation system. The first of the two [URL='https://en.wikipedia.org/wiki/Ubiquitin-like_protein']ubiquitin-like[/URL] conjugation systems involved in autophagy [URL='https://en.wikipedia.org/wiki/Covalent']covalently[/URL] binds the ubiquitin-like protein [URL='https://en.wikipedia.org/wiki/ATG12']Atg12[/URL] to [URL='https://en.wikipedia.org/wiki/ATG5']Atg5[/URL]. The resulting conjugate protein then binds [URL='https://en.wikipedia.org/wiki/ATG16L1']ATG16L1[/URL] to form an E3-like complex which functions as part of the second ubiquitin-like conjugation system.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid17986448-63'][63][/URL] This complex binds and activates [URL='https://en.wikipedia.org/wiki/Atg3']Atg3[/URL], which covalently attaches mammalian homologues of the ubiquitin-like yeast protein [URL='https://en.wikipedia.org/wiki/ATG8']ATG8[/URL] ([URL='https://en.wikipedia.org/wiki/MAP1LC3A']LC3A-C[/URL], GATE16, and GABARAPL1-3), the most studied being LC3 proteins, to the lipid [URL='https://en.wikipedia.org/wiki/Phosphatidylethanolamine']phosphatidylethanolamine[/URL] (PE) on the surface of autophagosomes.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid15169837-64'][64][/URL] Lipidated LC3 contributes to the closure of autophagosomes,[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid18768752-65'][65][/URL] and enables the docking of specific cargos and adaptor proteins such as Sequestosome-1/[URL='https://en.wikipedia.org/wiki/Sequestosome_1']p62[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid25483962-66'][66][/URL] The completed autophagosome then fuses with a [URL='https://en.wikipedia.org/wiki/Lysosome']lysosome[/URL] through the actions of multiple proteins, including SNAREs[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid19781582-67'][67][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid20089838-68'][68][/URL] and [URL='https://en.wikipedia.org/wiki/UVRAG']UVRAG[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid25533187-69'][69][/URL] Following the fusion LC3 is retained on the vesicle's inner side and degraded along with the cargo, while the LC3 molecules attached to the outer side are cleaved off by [URL='https://en.wikipedia.org/w/index.php?title=Atg4&action=edit&redlink=1']Atg4[/URL] and recycled.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid19322194-70'][70][/URL] The contents of the autolysosome are subsequently degraded and their building blocks are released from the vesicle through the action of [URL='https://en.wikipedia.org/wiki/Permease']permeases[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid17021250-71'][71][/URL] [URL='https://en.wikipedia.org/wiki/Sirtuin_1']Sirtuin 1[/URL] (SIRT1) stimulates autophagy by preventing [URL='https://en.wikipedia.org/wiki/Acetylation']acetylation[/URL] of proteins (via deacetylation) required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid32397145-72'][72][/URL] This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-73'][73][/URL] [HEADING=2]Functions[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=4']edit[/URL]][/HEADING] [HEADING=3]Nutrient starvation[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=5']edit[/URL]][/HEADING] Autophagy has roles in various cellular functions. One particular example is in yeasts, where the nutrient starvation induces a high level of autophagy. This allows unneeded proteins to be degraded and the amino acids recycled for the synthesis of proteins that are essential for survival.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Klionsky2002-74'][74][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-75'][75][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-76'][76][/URL] In higher eukaryotes, autophagy is induced in response to the nutrient depletion that occurs in animals at birth after severing off the trans-placental food supply, as well as that of nutrient starved cultured cells and tissues.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Kuma2004-77'][77][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Ohsumi2004-78'][78][/URL] Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Tsukada93-79'][79][/URL] Studies on the [I]apg[/I] mutants suggest that autophagy via autophagic bodies is indispensable for protein degradation in the vacuoles under starvation conditions, and that at least 15 APG genes are involved in autophagy in yeast.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Tsukada93-79'][79][/URL] A gene known as ATG7 has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in [I]atg7[/I]-deficient mice.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Ohsumi2004-78'][78][/URL] [HEADING=3]Infection[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=6']edit[/URL]][/HEADING] [URL='https://en.wikipedia.org/wiki/Vesicular_stomatitis_virus']Vesicular stomatitis virus[/URL] is believed to be taken up by the autophagosome from the cytosol and translocated to the [URL='https://en.wikipedia.org/wiki/Endosome']endosomes[/URL] where detection takes place by a [URL='https://en.wikipedia.org/wiki/Pattern_recognition_receptor']pattern recognition receptor[/URL] called [URL='https://en.wikipedia.org/wiki/Toll-like_receptor_7']toll-like receptor 7[/URL], detecting single stranded [URL='https://en.wikipedia.org/wiki/RNA']RNA[/URL]. Following activation of the toll-like receptor, intracellular signaling cascades are initiated, leading to induction of [URL='https://en.wikipedia.org/wiki/Interferon']interferon[/URL] and other antiviral [URL='https://en.wikipedia.org/wiki/Cytokine']cytokines[/URL]. A subset of viruses and bacteria subvert the autophagic pathway to promote their own replication.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-80'][80][/URL] [URL='https://en.wikipedia.org/wiki/Galectin-8']Galectin-8[/URL] has recently been identified as an intracellular "danger receptor", able to initiate autophagy against intracellular pathogens. When galectin-8 binds to a damaged [URL='https://en.wikipedia.org/wiki/Vacuole']vacuole[/URL], it recruits an autophagy adaptor such as [URL='https://en.wikipedia.org/wiki/CALCOCO2']NDP52[/URL] leading to the formation of an autophagosome and bacterial degradation.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-:3-81'][81][/URL] [HEADING=3]Repair mechanism[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=7']edit[/URL]][/HEADING] Autophagy degrades damaged organelles, cell membranes and proteins, and insufficient autophagy is thought to be one of the main reasons for the accumulation of damaged cells and [URL='https://en.wikipedia.org/wiki/Aging']aging[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Cuervo2005-82'][82][/URL] Autophagy and autophagy regulators are involved in response to lysosomal damage, often directed by [URL='https://en.wikipedia.org/wiki/Galectin']galectins[/URL] such as [URL='https://en.wikipedia.org/wiki/Galectin-3']galectin-3[/URL] and [URL='https://en.wikipedia.org/wiki/Galectin-8']galectin-8[/URL]. [HEADING=3]Programmed cell death[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=8']edit[/URL]][/HEADING] One of the mechanisms of [URL='https://en.wikipedia.org/wiki/Programmed_cell_death']programmed cell death[/URL] (PCD) is associated with the appearance of autophagosomes and depends on autophagy proteins. This form of cell death most likely corresponds to a process that has been morphologically defined as autophagic PCD. One question that constantly arises, however, is whether autophagic activity in dying cells is the cause of death or is actually an attempt to prevent it. Morphological and histochemical studies have not so far proved a causative relationship between the autophagic process and cell death. In fact, there have recently been strong arguments that autophagic activity in dying cells might actually be a survival mechanism.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-tavassoly-83'][83][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Shimizu2005-84'][84][/URL] Studies of the metamorphosis of insects have shown cells undergoing a form of PCD that appears distinct from other forms; these have been proposed as examples of autophagic cell death.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Osborne1993-85'][85][/URL] Recent pharmacological and biochemical studies have proposed that survival and lethal autophagy can be distinguished by the type and degree of regulatory signaling during stress particularly after viral infection.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Datan-86'][86][/URL] Although promising, these findings have not been examined in non-viral systems. [HEADING=2]Exercise[[URL='https://en.wikipedia.org/w/index.php?title=Autophagy&action=edit§ion=9']edit[/URL]][/HEADING] Autophagy is essential for basal [URL='https://en.wikipedia.org/wiki/Homeostasis']homeostasis[/URL]; it is also extremely important in maintaining [URL='https://en.wikipedia.org/wiki/Muscle']muscle[/URL] homeostasis during physical exercise.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pimd111111-87'][87][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Klionsky2011-88'][88][/URL] Autophagy at the molecular level is only partially understood. A study of mice shows that autophagy is important for the ever-changing demands of their nutritional and energy needs, particularly through the metabolic pathways of protein catabolism. In a 2012 study conducted by the [URL='https://en.wikipedia.org/wiki/University_of_Texas_Southwestern_Medical_Center']University of Texas Southwestern Medical Center[/URL] in [URL='https://en.wikipedia.org/wiki/Dallas']Dallas[/URL], mutant [URL='https://en.wikipedia.org/wiki/Mouse']mice[/URL] (with a knock-in mutation of [URL='https://en.wikipedia.org/wiki/BCL2']BCL2[/URL] phosphorylation sites to produce progeny that showed normal levels of basal autophagy yet were deficient in stress-induced autophagy) were tested to challenge this theory. Results showed that when compared to a control group, these mice illustrated a decrease in endurance and an altered [URL='https://en.wikipedia.org/wiki/Glucose']glucose[/URL] metabolism during acute exercise.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-He2012-89'][89][/URL] Another study demonstrated that [URL='https://en.wikipedia.org/wiki/Skeletal_muscle']skeletal muscle[/URL] fibers of [URL='https://en.wikipedia.org/wiki/Collagen_VI']collagen VI[/URL] in [URL='https://en.wikipedia.org/wiki/Knockout_mice']knockout mice[/URL] showed signs of degeneration due to an insufficiency of autophagy which led to an accumulation of damaged mitochondria and excessive [URL='https://en.wikipedia.org/wiki/Apoptosis']cell death[/URL].[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Grumati11-90'][90][/URL] Exercise-induced autophagy was unsuccessful however; but when autophagy was induced artificially post-exercise, the accumulation of damaged organelles in [URL='https://en.wikipedia.org/wiki/Collagen_VI']collagen VI[/URL] deficient muscle fibres was prevented and cellular homeostasis was maintained. Both studies demonstrate that autophagy induction may contribute to the beneficial metabolic effects of exercise and that it is essential in the maintaining of muscle homeostasis during exercise, particularly in collagen VI fibers.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-He2012-89'][89][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Klionsky2011-88'][88][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-Grumati11-90'][90][/URL] Work at the Institute for Cell Biology, University of Bonn, showed that a certain type of autophagy, i.e. [URL='https://en.wikipedia.org/wiki/Chaperone-assisted_selective_autophagy_(CASA)']chaperone-assisted selective autophagy (CASA)[/URL], is induced in contracting muscles and is required for maintaining the muscle [URL='https://en.wikipedia.org/wiki/Sarcomere']sarcomere[/URL] under mechanical tension.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid20060297-91'][91][/URL] The CASA chaperone complex recognizes mechanically damaged cytoskeleton components and directs these components through a [URL='https://en.wikipedia.org/wiki/Ubiquitin']ubiquitin[/URL]-dependent autophagic sorting pathway to lysosomes for disposal. This is necessary for maintaining muscle activity.[URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid20060297-91'][91][/URL][URL='https://en.wikipedia.org/wiki/Autophagy#cite_note-pmid23434281-92'][92][/URL] [HEADING=2][/HEADING] [/QUOTE]
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