The role of Bag3 in cell signaling

Abstract

Bag3 has been implicated in a wide variety of physiological processes from autophagy to aggresome formation and from cell transformation to survival. We argue that involvement of Bag3 in many of these processes is due to its distinct function in cell signaling. The structure of Bag3 suggests that it can serve as a scaffold that links molecular chaperones Hsp70 and small Hsps with components of a variety of signaling pathways. Major protein‐protein interaction motifs of Bag3 that recruit components of signaling pathways are WW domain and PXXP motif that interacts with SH3‐domain proteins. Furthermore, Hsp70‐Bag3 appears to be a sensor of abnormal polypeptides during the proteotoxic stress. It also serves as a sensor of a mechanical force during mechanotransduction. Common feature of these and probably certain other sensory mechanisms is that they represent responses to specific kinds of abnormal proteins, i.e. unfolded filamin A in case of mechanotransduction or stalled translating polypeptides in case of sensing proteasome inhibition. Overall Hsp70‐Bag3 module represents a novel signaling node that responds to multiple stimuli and controls multiple physiological processes.

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

“…Self-promoting, anti-apoptotic, and stress-induced Bag3 redirects the HSP70–substrate complex away from the proteosome and toward the lysosome [ 54 , 55 , 56 , 57 , 58 ]. This increases the relevance of Bag3 compared to other Bag proteins, as inhibition of apoptosis by autophagy is central to tumor resilience [ 154 ].…”

“…The WW domain is essential for the induction of chaperone-mediated autophagy, as it enables the interaction with the lysosome [ 54 ]. The PxxP chain of proline repeats interacts with the motor protein dynein [ 55 , 56 , 57 ]. With BAG connected to HSP70 and PxxP connected to dynein, the contained molecule is transported to LAMP2A where a WW interaction guides ALP.…”

Role of BAG5 in Protein Quality Control: Double-Edged Sword?

“…The members of this family contain a unique BAG domain which facilitates their interaction with the ATPase domain of molecular chaperone heat shock protein (HSP70) ( Arakawa et al, 2010 ). Interestingly, BAG3 protein has some additional domains like WW domains in addition to the BAG domain, which helps in interacting with other proteins ( Merabova et al, 2015 ; Sherman and Gabai, 2022 ). BAG family proteins play a significant role in regulating several physiological functions, like autophagy, UPS mediated protein degradation, and apoptosis ( Kögel et al, 2020 ).…”

HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy

“…For instance, they are, apparently indirectly, involved in the regulation of transcription (e.g., EMT-driving transcription factors), translation (e.g., HSPA5 in the ER), degradation/stabilization of proteins (e.g., p53), and a bunch of signaling pathways (see above Section 3 and Section 4 for details). In the case of cytosolic HSP70, its signaling functions seems to be mediated mainly by interaction with its co-chaperone BAG-3 (see [ 151 ] for review), but in the case of other HSP70s, it is not fully clear how such functions are realized in cancer cells and CSCs, although a number of cancer-related signaling axes that involve HSP70s have been described. In any event, such numerous indispensable functions of HSP70s in the tumor development and progression make them therapeutically attractive molecular targets since their suppression would affect many critical processes related to breast cancer (see next section).…”