Chaperone-assisted selective autophagy

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Autophagy (Greek: ‘self-eating’) was initially identified as a catabolic process for the unselective degradation of cellular content in lysosomes under starvation conditions.[1][2] However, autophagy also comprises selective degradation pathways, which depend on ubiquitin conjugation to initiate sorting to lysosomes.[3] Ubiquitin is a protein that assists in controlling the functions of other proteins within the body. A protein can have its function altered when it binds with an ubiquitin molecule and this process is called ubiquitination. There are three steps to ubiquitination: ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, and ubiquitin ligase.[4] Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.[5][6][7][8] In the case of chaperone-assisted selective autophagy, dysfunctional, nonnative proteins are recognized by molecular chaperones and become ubiquitinated by chaperone-associated ubiquitin ligases, and the protein to be destroyed is tagged by a chaperone protein. 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.[5][6][7][8] Mutations in the genes responsible for the chaperone-assisted selective autophagy complex can result in myopathies and neurodegenerative conditions.[9]

Components and mechanism[edit]

The chaperone-assisted selective autophagy complex comprises the molecular chaperones HSPA8 and HSPB8, and the cochaperones BAG3 and STUB1.[6] 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.[9] 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.[3] 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.[5] 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.[9] 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.[9] 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.[9]

Clients and physiological role[edit]

Proteins that are degraded by chaperone-assisted selective autophagy include pathogenic forms of the Huntingtin protein, which cause Huntington's disease.[8] 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.[7] 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.[5][6] 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.[10][11][12]

References[edit]

  1. ^ Reggiori F, Klionsky DJ (February 2002). "Autophagy in the eukaryotic cell". Eukaryotic Cell. 1 (1): 11–21. doi:10.1128/EC.01.1.11-21.2002. PMC 118053. PMID 12455967.
  2. ^ Levine B, Klionsky DJ (April 2004). "Development by self-digestion: molecular mechanisms and biological functions of autophagy". Dev. Cell. 6 (4): 463–77. doi:10.1016/S1534-5807(04)00099-1. PMID 15068787.
  3. ^ a b Shaid S, Brandts CH, Serve H, Dikic I (January 2013). "Ubiquitination and selective autophagy". Cell Death Differ. 20 (1): 21–30. doi:10.1038/cdd.2012.72. PMC 3524631. PMID 22722335.
  4. ^ B.Pharm, Yolanda Smith (2010-11-04). "What is Ubiquitin?". News-Medical. Retrieved 2024-05-03.
  5. ^ a b c d 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 (February 2013). "Cellular Mechanotransduction Relies on Tension-Induced and Chaperone-Assisted Autophagy". Curr Biol. 23 (5): 430–35. doi:10.1016/j.cub.2013.01.064. PMID 23434281.
  6. ^ a b c d Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J (January 2010). "Chaperone-assisted selective autophagy is essential for muscle maintenance". Curr Biol. 20 (2): 143–8. doi:10.1016/j.cub.2009.11.022. PMID 20060297.
  7. ^ a b c Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C (April 2009). "Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3". EMBO J. 28 (7): 889–901. doi:10.1038/emboj.2009.29. PMC 2647772. PMID 19229298.
  8. ^ a b c Carra S, Seguin SJ, Landry J (January 2008). "HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy". Autophagy. 4 (2): 237–9. doi:10.4161/auto.5407. PMID 18094623.
  9. ^ a b c d e Tedesco, Barbara; Vendredy, Leen; Timmerman, Vincent; Poletti, Angelo (2023-06-03). "The chaperone-assisted selective autophagy complex dynamics and dysfunctions". Autophagy. 19 (6): 1619–1641. doi:10.1080/15548627.2022.2160564. ISSN 1554-8627. PMC 10262806. PMID 36594740.{{cite journal}}: CS1 maint: PMC format (link)
  10. ^ Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, Engel AG (January 2009). "Mutation in BAG3 causes severe dominant childhood muscular dystrophy". Ann Neurol. 65 (1): 83–9. doi:10.1002/ana.21553. PMC 2639628. PMID 19085932.
  11. ^ Homma S, Iwasaki M, Shelton GD, Engvall E, Reed JC, Takayama S (September 2006). "BAG3 deficiency results in fulminant myopathy and early lethality". Am J Pathol. 169 (3): 761–73. doi:10.2353/ajpath.2006.060250. PMC 1698816. PMID 16936253.
  12. ^ 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 (February 2009). "Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy". Nat Genet. 44 (4): 450–5. doi:10.1038/ng.1103. PMC 3315599. PMID 22366786.
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