The chaperone-assisted selective autophagy complex dynamics and dysfunctions

Each protein must be synthesized with the correct amino acid sequence, folded into its native structure, and transported to a relevant subcellular location and protein complex. If any of these steps fail, the cell has the capacity to break down aberrant proteins to maintain protein homeostasis (also called proteostasis). All cells possess a set of well-characterized protein quality control systems to minimize protein misfolding and the damage it might cause. Autophagy, a conserved pathway for the degradation of long-lived proteins, aggregates, and damaged organelles, was initially characterized as a bulk degradation pathway. However, it is now clear that autophagy also contributes to intracellular homeostasis by selectively degrading cargo material. One of the pathways involved in the selective removal of damaged and misfolded proteins is chaperone-assisted selective autophagy (CASA). The CASA complex is composed of three main proteins (HSPA, HSPB8 and BAG3), essential to maintain protein homeostasis in muscle and neuronal cells. A failure in the CASA complex, caused by mutations in the respective coding genes, can lead to (cardio)myopathies and neurodegenerative diseases. Here, we summarize our current understanding of the CASA complex and its dynamics. We also briefly discuss how CASA complex proteins are involved in disease and may represent an interesting therapeutic target.

Automated summary

Each protein must be correctly synthesized, folded, and transported to its appropriate location. Failure in these steps can lead to protein misfolding and potential damage. Cells have well-characterized protein quality control systems, including autophagy and chaperone-assisted selective autophagy (CASA), to minimize such issues. The CASA complex, composed of HSPA, HSPB8, and BAG3 proteins, is essential for maintaining protein homeostasis and mutations in these genes can result in (cardio)myopathies and neurodegenerative diseases. This article summarizes the current understanding of the CASA complex and discusses its involvement in diseases and potential therapeutic targets.