Abstract
BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins by regulating their turnover via the two major protein degradation pathways, i.e. proteasomal degradation and macroautophagy. On the one hand, BAG3 competes with BAG1 for binding to HSP70, thereby preventing the proteasomal degradation of its client proteins. By functionally interacting with HSP70 and LC3, BAG3 also delivers polyubiquitinated proteins to the autophagy pathway. BAG3 exerts a number of key physiological functions, including an involvement in cellular stress responses, proteostasis, cell death regulation, development, and cytoskeletal dynamics. Conversely, aberrant BAG3 function/expression has pathophysiological relevance correlated to cardiomyopathies, neurodegeneration, and cancer. Evidence obtained in recent years underscores the fact that BAG3 drives several key hallmarks of cancer, including cell adhesion, metastasis, angiogenesis, enhanced autophagic activity, and apoptosis inhibition. This review provides a state-of-the-art overview on the role of BAG3 in stress and therapy resistance of cancer, with a particular focus on BAG3-dependent modulation of apoptotic signaling and autophagic/lysosomal activity.
Highlights
The multifunctional heat shock protein 70 (HSP70) co-chaperone and anti-apoptotic protein BAG3 is a well investigated member of the Bcl-2-associated athanogene (BAG) protein family [1,2,3]
Since BAG3 competes with BAG1 for binding to the ATPase domain of HSP70, BAG3 can interfere with the HSP70/BAG1-dependent delivery of clients to proteasomal degradation
Apoptosis is characterized by a cascade of molecular events that are initiated by distinct upstream signals and culminate in the activation of effector caspases, the major executors of BAG3 is centrally involved in regulation of both major cellular protein degradation pathways, proteasomal degradation, and autophagy, and plays a key physiological role in cellular proteostasis [1,2,3]
Summary
The multifunctional HSP70 co-chaperone and anti-apoptotic protein BAG3 ( called Bis [BCL-2 interacting death suppressor] and CAIR-1) is a well investigated member of the Bcl-2-associated athanogene (BAG) protein family [1,2,3]. Apoptosis is characterized by a cascade of molecular events that are initiated by distinct upstream signals and culminate in the activation of effector caspases, the major executors of BAG3 is centrally involved in regulation of both major cellular protein degradation pathways, proteasomal degradation, and autophagy, and plays a key physiological role in cellular proteostasis [1,2,3]. Since BAG3 is capable of promoting cell survival signaling by interacting with distinct client proteins in complex with HSP70, this BAG3 overexpression in general contributes to apoptosis resistance of the tumors [8]. The binding of BAG3 to GLS prevented its proteosomal degradation, whereas autophagy was hypothesized to be induced via ammonia that is derived from glutaminolysis, as was shown previously [31], indicating that BAG3 is a central factor bridging cancer metabolism and autophagy
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