Morsink Margaretha A J, Watkins Josephine M, Zhu Katelyn, Zhang Xiaokan, Luo Lori J, Fine Barry M, Wang Bryan Z, Vunjak-Novakovic Gordana
Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Department of Medicine, Columbia University, New York, NY, USA.
J Mol Cell Cardiol. 2025 Aug;205:13-23. doi: 10.1016/j.yjmcc.2025.06.003. Epub 2025 Jun 5.
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.
转化生长因子β（TGF-β）是心脏纤维化的主要调节因子，部分是通过II型TGF-β受体（TGFBR2）实现的，该受体在配体结合后启动信号传导。我们之前鉴定出伴侣蛋白Bcl2相关抗凋亡基因（BAG3）是TGFBR2的调节剂，通过泛素化和蛋白酶体降解发挥作用。然而，TGFBR2的E3连接酶尚不清楚。利用诱导多能干细胞衍生的心脏成纤维细胞，我们鉴定出热休克蛋白70（HSP70）的C末端相互作用蛋白（CHIP）是BAG3在心脏成纤维细胞中用于降解TGFBR2的E3泛素连接酶。CHIP的过表达显著降低了TGFBR2的稳定性，而抑制CHIP则导致对TGF-β的敏感性增加，并随后促进纤维化程序。此外，BAG3-HSP70相互作用对这一过程至关重要，因为该轴的破坏增加了TGFBR2的稳定性和对TGF-β信号传导的敏感性。总之，这些发现表明BAG3-HSP70-CHIP轴控制心脏成纤维细胞中的TGF-β信号传导，并可能成为心脏纤维化的新治疗靶点。
