The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China; State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China.
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China.
Biochem Biophys Res Commun. 2014 Mar 28;446(1):387-92. doi: 10.1016/j.bbrc.2014.02.124. Epub 2014 Mar 5.
Transforming growth factor-β (TGF-β) signaling plays an important role in regulation of a wide variety of cellular processes. Canonical TGF-β signaling is mediated by Smads which were further regulated by several factors. We previously reported that E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein, also named Stub1) controlled the sensitivity of TGF-β signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. Here, we present evidence that Hsp70 and Hsp90 regulate the complex formation of Smad3/CHIP. Furthermore, we observed that over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3, which finally enhances TGF-β signaling. In contrast, over-expressed Hsp90 antagonizes CHIP mediated Smad3 ubiquitination and degradation and desensitizes cells in response to TGF-β signaling. Taken together, our data reveal an opposite role of Hsp70 and Hsp90 in regulating TGF-β signaling by implicating CHIP-mediated Smad3 ubiquitination and degradation. This study provides a new insight into understanding the regulation of the TGF-β signaling by chaperones.
转化生长因子-β（TGF-β）信号在调节多种细胞过程中起着重要作用。经典的 TGF-β信号通过 Smads 介导，Smads 进一步受几种因素的调节。我们之前的研究报告称，E3 泛素连接酶 CHIP（Hsc70 相互作用蛋白的羧基末端，也称为 Stub1）通过泛素介导的降解来调节 Smad3 的基础水平，从而控制 TGF-β信号的敏感性。在这里，我们提供了证据表明 Hsp70 和 Hsp90 调节 Smad3/CHIP 复合物的形成。此外，我们观察到过表达的 Hsp70 或用格尔德霉素（GA）抑制 Hsp90 会促进 CHIP 诱导的 Smad3 泛素化和降解，最终增强 TGF-β信号。相反，过表达的 Hsp90 拮抗 CHIP 介导的 Smad3 泛素化和降解，并使细胞对 TGF-β信号脱敏。总之，我们的数据揭示了 Hsp70 和 Hsp90 在通过 CHIP 介导的 Smad3 泛素化和降解来调节 TGF-β信号方面的相反作用。本研究为理解伴侣蛋白对 TGF-β信号的调节提供了新的见解。
