Biology:Chaperone-assisted selective autophagy
Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.[1][2][3][4] Autophagy (Greek: ‘self-eating’) was initially identified as a catabolic process for the unselective degradation of cellular content in lysosomes under starvation conditions.[5][6] However, autophagy also comprises selective degradation pathways, which depend on ubiquitin conjugation to initiate sorting to lysosomes.[7] In the case of chaperone-assisted selective autophagy, dysfunctional, nonnative proteins are recognized by molecular 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.[1][2][3][4]
Components and mechanism
The chaperone-assisted selective autophagy complex comprises the molecular chaperones HSPA8 and HSPB8, and the cochaperones BAG3 and STUB1.[2] 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.[7] 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.[1] 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.[4] 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.[3] 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.[1][2] 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.[8][9][10]
References
- ↑ 1.0 1.1 1.2 1.3 "Cellular Mechanotransduction Relies on Tension-Induced and Chaperone-Assisted Autophagy". Curr Biol 23 (5): 430–35. February 2013. doi:10.1016/j.cub.2013.01.064. PMID 23434281.
- ↑ 2.0 2.1 2.2 2.3 "Chaperone-assisted selective autophagy is essential for muscle maintenance". Curr Biol 20 (2): 143–8. January 2010. doi:10.1016/j.cub.2009.11.022. PMID 20060297.
- ↑ 3.0 3.1 3.2 "Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3". EMBO J 28 (7): 889–901. April 2009. doi:10.1038/emboj.2009.29. PMID 19229298.
- ↑ 4.0 4.1 4.2 "HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy". Autophagy 4 (2): 237–9. January 2008. doi:10.4161/auto.5407. PMID 18094623.
- ↑ "Autophagy in the eukaryotic cell". Eukaryotic Cell 1 (1): 11–21. February 2002. doi:10.1128/EC.01.1.11-21.2002. PMID 12455967.
- ↑ "Development by self-digestion: molecular mechanisms and biological functions of autophagy". Dev. Cell 6 (4): 463–77. April 2004. doi:10.1016/S1534-5807(04)00099-1. PMID 15068787.
- ↑ 7.0 7.1 "Ubiquitination and selective autophagy". Cell Death Differ 20 (1): 21–30. January 2013. doi:10.1038/cdd.2012.72. PMID 22722335.
- ↑ "Mutation in BAG3 causes severe dominant childhood muscular dystrophy". Ann Neurol 65 (1): 83–9. January 2009. doi:10.1002/ana.21553. PMID 19085932.
- ↑ "BAG3 deficiency results in fulminant myopathy and early lethality". Am J Pathol 169 (3): 761–73. September 2006. doi:10.2353/ajpath.2006.060250. PMID 16936253.
- ↑ "Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy". Nat Genet 44 (4): 450–5. February 2009. doi:10.1038/ng.1103. PMID 22366786.
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