Chaperone-assisted proteostasis is essential for mechanotransduction in mammalian cells

Abstract

Maintaining the dynamic proteome of a living cell in the face of an ever-changing environment depends on a fine-tuned balance of protein synthesis and protein degradation. Molecular chaperones exert key functions during protein homeostasis (proteostasis). They associate with nonnative client proteins following synthesis or damage and facilitate client sorting and folding. When client proteins are terminally misfolded, chaperones cooperate with protein degradation systems to dispose of such clients. This dual proteostasis activity of chaperones is essential for maintaining cell function under normal growth conditions and becomes even more important under stress conditions such as heat and oxidative stress. The recent identification of chaperone-assisted selective autophagy (CASA) as a tension-induced autophagy pathway highlights the critical role of molecular chaperones in mechanically strained cells and tissues. The CASA complex, assembled by the cochaperone BAG3, coordinates protein degradation and protein synthesis in response to mechanical force. Here we describe the composition and function of this chaperone complex in mammals and discuss its relevance for tissue homeostasis and the regulation of cell adhesion, migration and proliferation. We provide a unifying concept for the function of BAG3, which integrates its involvement in muscle maintenance, tumor formation and virus infection.

Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress

“…Finally, we sought to identify the functional domains of BAG3 that mediate its interaction with eVP40 and mVP40. BAG3 contains a number of functional domains including: a single N-terminal WW-domain, two IPV regions that bind to HspB8 and function in protein quality control, multiple PxxP motifs that binds to SH3 domains, and a C-terminal BAG domain that interacts with the ATPase domain of HSP70 ( Fig 4A) [41][42][43][44][45]. Briefly, HEK293T cells were co- BAG3 interacts with eVP40 in a PPxY-dependent manner.…”

Imbalances in protein homeostasis caused by mutant desmin

“…Furthermore, in both genotypes the band corresponding to LC3‐II (lower band; autophagosome membrane‐bound form) was markedly elevated (Figure E , G ). Subsequently, we examined the protein levels of filamin‐C and BAG‐3, both of which are essential components of the CASA system , in soleus muscle tissue and 10 day differentiated myotubes derived from hetero‐ and homozygous R349P desmin knock‐in mice as well as wild‐type siblings. While the protein levels of filamin‐C and BAG‐3 were markedly increased only in homozygous soleus muscle tissue (Figure A , B ), they were more abundant compared to wild‐type in both hetero‐ and homozygous desminopathy myotubes (Figure C , D ).…”

To deliver or to degrade – an interplay of the ubiquitin–proteasome system, autophagy and vesicular transport in plants

“…The role of co‐chaperones and adaptor proteins in both protein degradation mechanisms is well described in mammals (reviewed by Ulbricht et al . and McClellan et al . ).…”

“…In this step, Ub is used as a common mechanism for tagging. The role of co-chaperones and adaptor proteins in both protein degradation mechanisms is well described in mammals (reviewed by Ulbricht et al [184] and McClellan et al [185]). Co-chaperones from the BCL2-associated athanogene (BAG) family can target proteins either for refolding or to the clearence machineries.…”