De-ubiquitinating enzyme, USP11, promotes transforming growth factor β-1 signaling through stabilization of transforming growth factor β receptor II.
De-ubiquitinating enzyme, USP11, promotes transforming growth factor β-1 signaling through stabilization of transforming growth factor β receptor II.
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去泛素化酶USP11，通过稳定转化生长因子β受体II来促进生长因子β-1信号传导。
DOI：
10.1038/cddis.2016.371
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发表时间：
2016-11-17
影响因子：
9
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Jacko AM;Nan L;Li S;Tan J;Zhao J;Kass DJ;Zhao Y
转化生长因子β-1（transforming growth factor β-1，TGFβ-1）信号通路在肺纤维化的发病机制中起着重要作用。两种TGFβ-1受体TβRI和TβRII介导该途径。由泛素/去泛素化系统介导的TβRI蛋白稳定性已得到充分研究;然而，TβRII的分子调控仍不清楚。我们发现去泛素化酶USP 11通过去泛素化和稳定TβRII促进TGFβ 1信号传导。我们阐明了米托蒽醌（MTX），一种USP 11抑制剂，在TGFβ-1信号转导减弱中的作用。USP 11的抑制或下调导致TβRII遍在蛋白化增加和TβRII稳定性降低。随后，TGFβ-1信号传导大大减弱，如SMAD 2/3水平以及纤连蛋白（FN）和平滑肌肌动蛋白（SMA）磷酸化水平的降低所示。USP 11的过表达减少了TβRII的泛素化，增加了TβRII的稳定性，从而提高了SMAD 2/3的磷酸化以及FN和SMA的最终表达。此外，在博来霉素激发小鼠和IPF患者的肺组织中检测到USP 11和TβRII的表达升高。因此，USP 11可能通过稳定TβRII和促进TGFβ 1信号通路参与肺纤维化的发病机制。本研究为开发USP 11抑制剂作为肺纤维化潜在抗纤维化药物提供了机制证据。
The transforming growth factor β-1 (TGFβ-1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis. Two TGFβ-1 receptors, TβRI and TβRII, mediate this pathway. TβRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TβRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGFβ-1 signaling through de-ubiquitination and stabilization of TβRII. We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGFβ-1 signaling. Inhibition or downregulation of USP11 results in increases in TβRII ubiquitination and reduction of TβRII stability. Subsequently, TGFβ-1 signaling is greatly attenuated, as shown by the decreases in phosphorylation of SMAD2/3 levels as well as that of fibronectin (FN) and smooth muscle actin (SMA). Overexpression of USP11 reduces TβRII ubiquitination and increases TβRII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA. Further, elevated expression of USP11 and TβRII were detected in lung tissues from bleomycin-challenged mice and IPF patients. Therefore, USP11 may contribute to the pathogenesis of pulmonary fibrosis by stabilization of TβRII and promotion of TGFβ-1 signaling. This study provides mechanistic evidence for development of USP11 inhibitors as potential antifibrotic drugs for pulmonary fibrosis.