BAG3

BAG3, short for BCL2-associated athanogene 3, is a co-chaperone protein that participates in chaperone-assisted proteostasis. It is a member of the BAG family and functions as a regulator of protein quality control, particularly under cellular stress.

In terms of structure, BAG3 contains a conserved BAG domain at the C-terminus that binds Hsp70/Hsc70. It also engages small heat shock proteins through additional interaction motifs, enabling the formation of proteostatic complexes. Through these interactions, BAG3 participates in chaperone-assisted selective autophagy (CASA), a pathway that targets misfolded or damaged proteins for autophagic degradation, with a focus on cytoskeletal components and other mechanically stressed proteins.

BAG3 is widely expressed but shows particularly high activity in cardiac and skeletal muscle, where it helps maintain sarcomeric integrity and proteostasis during mechanical load. In physiological conditions, BAG3 cooperates with other chaperones and co-chaperones to prevent protein aggregation and to regulate apoptosis and stress signaling.

Genetic mutations in BAG3 are associated with human disease. Pathogenic BAG3 variants can cause familial dilated cardiomyopathy, often with early-onset heart failure and variable skeletal muscle involvement. Other BAG3 mutations have been linked to myofibrillar myopathy and distal motor neuropathy. In addition to inherited conditions, altered BAG3 expression has been observed in various cancers and is the subject of research due to its potential impact on cell survival and response to therapy.

Overall, BAG3 plays a central role in protein quality control and cell survival, with important implications for heart and muscle biology and for disease processes involving proteostasis.