The BAG3-HSP70-CHIP axis controls the degradation of TGFBR2 in cardiac fibroblasts

Transforming Growth Factor Beta (TGF-β) is a master regulator of cardiac fibrosis, in part through the type II TGF-β receptor (TGFBR2) which initiates signaling after ligand binding. We previously identified the co-chaperone protein Bcl2-associated athanogene (BAG3) as a modulator of TGFBR2 through ubiquitination and proteasomal degradation. However, the E3 ligase of TGFBR2 was not known. Using induced pluripotent stem cell-derived cardiac fibroblasts, we identified C-terminal interacting protein of HSP70 (CHIP) as an E3 ubiquitin ligase utilized by BAG3 for TGFBR2 degradation in cardiac fibroblasts. Overexpression of CHIP significantly decreased TGFBR2 stability, while inhibition of CHIP led to increased sensitivity to TGF-β and subsequent promotion of a fibrogenic program. Further, the BAG3-HSP70 interaction was crucial to this process, as disruption of the axis increased TGFBR2 stability and sensitivity to TGF-β signaling. Together, these findings demonstrate that the BAG3-HSP70-CHIP axis controls TGF-β signaling in cardiac fibroblasts and could serve as a new therapeutic target for cardiac fibrosis.