Chaperone-assisted selective autophagy

'''Chaperone-assisted selective autophagy''' is a cellular process for the selective, [[ubiquitin]]-dependent degradation of [[Chaperone (protein)|chaperone]]-bound [[proteins]] in [[lysosomes]].<ref name="pmid23434281">{{cite journal | vauthors = Ulbricht A, Eppler FJ, Tapia VE, van der Ven PF, Hampe N, Hersch N, Vakeel P, Stadel D, Haas A, Saftig P, Behrends C, Fürst DO, Volkmer R, Hoffmann B, Kolanus W, Höhfeld J | display-authors = 6 | title = Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy | journal = Current Biology | volume = 23 | issue = 5 | pages = 430–435 | date = March 2013 | pmid = 23434281 | doi = 10.1016/j.cub.2013.01.064 | doi-access = free | bibcode = 2013CBio...23..430U }}</ref><ref name="pmid20060297">{{cite journal | vauthors = Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J | display-authors = 6 | title = Chaperone-assisted selective autophagy is essential for muscle maintenance | journal = Current Biology | volume = 20 | issue = 2 | pages = 143–148 | date = January 2010 | pmid = 20060297 | doi = 10.1016/j.cub.2009.11.022 | doi-access = free | bibcode = 2010CBio...20..143A }}</ref><ref name="pmid19229298">{{cite journal | vauthors = Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C | title = Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3 | journal = The EMBO Journal | volume = 28 | issue = 7 | pages = 889–901 | date = April 2009 | pmid = 19229298 | pmc = 2647772 | doi = 10.1038/emboj.2009.29 }}</ref><ref name="pmid18094623">{{cite journal | vauthors = Carra S, Seguin SJ, Landry J | title = HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy | journal = Autophagy | volume = 4 | issue = 2 | pages = 237–239 | date = February 2008 | pmid = 18094623 | doi = 10.4161/auto.5407 | doi-access = free | hdl = 11380/703945 | hdl-access = free }}</ref>

[[Autophagy]] (Greek: ‘self-eating’) was initially identified as a catabolic process for the unselective degradation of cellular content in lysosomes under starvation conditions.<ref name="pmid12455967">{{cite journal | vauthors = Reggiori F, Klionsky DJ | title = Autophagy in the eukaryotic cell | journal = Eukaryotic Cell | volume = 1 | issue = 1 | pages = 11–21 | date = February 2002 | pmid = 12455967 | pmc = 118053 | doi = 10.1128/EC.01.1.11-21.2002 }}</ref><ref name="pmid15068787">{{cite journal | vauthors = Levine B, Klionsky DJ | title = Development by self-digestion: molecular mechanisms and biological functions of autophagy | journal = Developmental Cell | volume = 6 | issue = 4 | pages = 463–477 | date = April 2004 | pmid = 15068787 | doi = 10.1016/S1534-5807(04)00099-1 | doi-access = free }}</ref> However, autophagy also comprises selective degradation pathways, which depend on [[ubiquitin]] conjugation to initiate sorting to lysosomes.<ref name="pmid22722335">{{cite journal | vauthors = Shaid S, Brandts CH, Serve H, Dikic I | title = Ubiquitination and selective autophagy | journal = Cell Death and Differentiation | volume = 20 | issue = 1 | pages = 21–30 | date = January 2013 | pmid = 22722335 | pmc = 3524631 | doi = 10.1038/cdd.2012.72 }}</ref> In the case of chaperone-assisted selective autophagy, dysfunctional, nonnative proteins are recognized by molecular [[Chaperone (protein)|chaperones]] and become ubiquitinated by chaperone-associated [[ubiquitin]] ligases. The ubiquitinated proteins are enclosed in autophagosomes, which eventually fuse with lysosomes, leading to the degradation of the dysfunctional proteins. Chaperone-assisted selective autophagy is a vital part of the cellular protein quality control system. It is essential for protein homeostasis ([[proteostasis]]) in [[neurons]] and in mechanically strained cells and tissues such as [[skeletal muscle]], [[heart]] and [[lung]].<ref name="pmid23434281"/><ref name="pmid20060297"/><ref name="pmid19229298"/><ref name="pmid18094623"/>

==Components and mechanism== The chaperone-assisted selective autophagy complex comprises the molecular chaperones [[HSPA8]] and [[HSPB8]], and the cochaperones [[BAG3]] and [[STUB1]].<ref name="pmid20060297"/> The cochaperone BAG3 plays a vital role in maintaining homeostasis. BAG3 facilitates the cooperation of HSPA8 and HSPB8 during the recognition of nonnative client proteins. HSPBs are chaperones that interact with misfolded substrates without the need for ATP to avoid aggregation. HSPB8 interacts with other HSPBs weakly and mostly forms homodimers.<ref name="Tedesco_2023">{{cite journal | vauthors = Tedesco B, Vendredy L, Timmerman V, Poletti A | title = The chaperone-assisted selective autophagy complex dynamics and dysfunctions | journal = Autophagy | volume = 19 | issue = 6 | pages = 1619–1641 | date = June 2023 | pmid = 36594740 | pmc = 10262806 | doi = 10.1080/15548627.2022.2160564 }}</ref> STUB1 mediates the [[ubiquitination]] of the chaperone-bound client, which induces the recruitment of the autophagic ubiquitin adaptor [[SQSTM1]]. The adaptor simultaneously interacts with the ubiquitinated client and autophagosome membrane precursors, thereby inducing the autophagic engulfment of the client.<ref name="pmid22722335"/> Autophagosome formation during chaperone-assisted selective autophagy depends on an interaction of [[BAG3]] with [[SYNPO2]], which triggers the cooperation with a [[VPS18]]-containing protein complex that mediates the fusion of autophagosome membrane precursors.<ref name="pmid23434281"/> The formed autophagosomes finally fuse with lysosomes, resulting in client degradation. There are 5 main components for the chaperone-assisted selective autophagy complex are the molecular chaperones, autophagy receptors, autophagy equipment, lysosomes, and the substrates. The damaged and misfolded proteins inside the cell are recognized by the molecular chaperones, which afterwards bind to them. The receptors attach themselves to substrates that are connected to chaperones. This helps the substrate degrade. The chaperone-assisted selective autophagy substrates could be sent to specific areas like aggresomes for additional processing.<ref name="Tedesco_2023" /> The aggresomes are stress-induced juxta-nuclear inclusion bodies that requires an intact microtubular network to colocalize misfolded proteins, molecular chaperones, and UPS components at the microtubule organizing center.<ref name="Tedesco_2023" /> The chaperone-assisted selective autophagy is dependent on the formation of a heteromeric complex. This consists of the heat shock proteins and BAG3. The BAG family has 6 cochaperone members and BAG1 was identified as an interactor of Bcl-2 proteins which is an anti-apoptotic protein. The activation of HSF1 is the primary mechanism by which heat shock, proteasome inhibition, oxidative stress, and other stressors increase BAG3 expression.<ref name="Tedesco_2023" />

The chaperone-assisted selective autophagy complex comprises the molecular chaperones [[HSPA8]] and [[HSPB8]], and the cochaperones [[BAG3]] and [[STUB1]].<ref name="pmid20060297"/> BAG3 facilitates the cooperation of HSPA8 and HSPB8 during the recognition of nonnative client proteins. STUB1 mediates the [[ubiquitination]] of the chaperone-bound client, which induces the recruitment of the autophagic ubiquitin adaptor [[SQSTM1]]. The adaptor simultaneously interacts with the ubiquitinated client and autophagosome membrane precursors, thereby inducing the autophagic engulfment of the client.<ref name="pmid22722335"/> Autophagosome formation during chaperone-assisted selective autophagy depends on an interaction of [[BAG3]] with [[SYNPO2]], which triggers the cooperation with a [[VPS18]]-containing protein complex that mediates the fusion of autophagosome membrane precursors.<ref name="pmid23434281"/> The formed autophagosomes finally fuse with lysosomes, resulting in client degradation.

==Clients and physiological role== Proteins that are degraded by chaperone-assisted selective autophagy include pathogenic forms of the [[Huntingtin]] protein, which cause [[Huntington's disease]].<ref name="pmid18094623"/> Furthermore, the expression of the cochaperone BAG3 is upregulated in aged neuronal cells, which correlates with an increased necessity to dispose oxidatively damaged proteins through autophagy.<ref name="pmid19229298"/> Chaperone-assisted selective autophagy is thus essential for [[proteostasis]] in [[neurons]].

In mechanically strained cells and tissues, chaperone-assisted selective autophagy mediates the degradation of the [[actin]]-crosslinking protein [[filamin]].<ref name="pmid23434281"/><ref name="pmid20060297"/> Mechanical tension results in unfolding of filamin, leading to recognition by the chaperone complex and to the autophagic degradation of damaged filamin. This is a prerequisite for the maintenance of the [[actin]] cytoskeleton in mechanically strained cells and tissues. Impairment of chaperone-assisted selective autophagy in patients and animal models causes [[muscle dystrophy]] and [[cardiomyopathy]].<ref name="pmid19085932">{{cite journal | vauthors = Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, Engel AG | title = Mutation in BAG3 causes severe dominant childhood muscular dystrophy | journal = Annals of Neurology | volume = 65 | issue = 1 | pages = 83–89 | date = January 2009 | pmid = 19085932 | pmc = 2639628 | doi = 10.1002/ana.21553 }}</ref><ref name="pmid16936253">{{cite journal | vauthors = Homma S, Iwasaki M, Shelton GD, Engvall E, Reed JC, Takayama S | title = BAG3 deficiency results in fulminant myopathy and early lethality | journal = The American Journal of Pathology | volume = 169 | issue = 3 | pages = 761–773 | date = September 2006 | pmid = 16936253 | pmc = 1698816 | doi = 10.2353/ajpath.2006.060250 }}</ref><ref name="pmid22366786">{{cite journal | vauthors = Sarparanta J, Jonson PH, Golzio C, Sandell S, Luque H, Screen M, McDonald K, Stajich JM, Mahjneh I, Vihola A, Raheem O, Penttilä S, Lehtinen S, Huovinen S, Palmio J, Tasca G, Ricci E, Hackman P, Hauser M, Katsanis N, Udd B | display-authors = 6 | title = Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy | journal = Nature Genetics | volume = 44 | issue = 4 | pages = 450–5 | date = February 2012 | pmid = 22366786 | pmc = 3315599 | doi = 10.1038/ng.1103 }}</ref>

== References == {{reflist}}

[[Category:Cell biology]]