Chaperone-assisted selective autophagy in Health and Disease

Chaperone-assisted selective autophagy (CASA) is a degradative pathway fundamental for the removal of misfolded and damaged proteins in striatal muscle cells and neurons. CASA is mediated by a protein complex composed of chaperones heat shock protein family B (small) member 8 (HSPB8) and heat shock protein family A (HSPA), interacting with BAG cochaperone 3 (BAG3), and STIP1 homology and U-Box containing protein 1 (STUB1). Misfolded substrates bound to the CASA complex undergo refolding, or, when refolding is not possible or proteins are damaged, they are ubiquitinated by the ubiquitin ligase STUB1. Ubiquitinated substrates are subsequently recognized by sequestosome-1/p62, which promotes their engulfment into autophagosomes for lysosomal degradation. CASA physiologically ensures the maintenance of Z-discs by favoring the recycling of structural proteins in skeletal and cardiac muscle cells. In pathological conditions, CASA enhancement favors the disposal of protein aggregates associated with neurodegenerative and neuromuscular diseases. Mutations in CASA members have been associated with neuropathies, myopathies, and cardiomyopathies. Our previous studies on selected mutants of BAG3 and HSPB8 causative of neuromyopathies demonstrated that one pathogenic mechanism lies in a toxic function gain. Indeed, we demonstrated that mutants HSPB8 and BAG3 exhibit increased insolubility and aggregation propensity and sequester other members of the CASA complex. This results in a defective CASA complex activity in degrading its client proteins and a general perturbation of intracellular proteostasis. Overall, these data suggest that HSPB8 and BAG3 aggregation is a key event for the development of CASA-related neuromyopathies.