De-ubiquitinating enzyme, USP11, promotes transforming growth factor β-1 signaling through stabilization of transforming growth factor β receptor II

Abstract

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.

Ubiquitin-specific protease 11 serves as a marker of poor prognosis and promotes metastasis in hepatocellular carcinoma

“…The deubiquitinase activity of USP11 is involved in the regulation of BRCA2 in response to DNA damage, leading to increased survival of cancer cells [8]. USP11 plays an important role in the downregulation of TNFα-mediated NF-κB activation by modulating IκB kinase α (IKKα) stability [9], and promotes transforming growth factor β-1 (TGFβ-1) signaling through de-ubiquitination and stabilization of TβRII [10]. USP11 can also modulate TGF-β signaling by deubiquitinating the type I TGF-β receptor ALK5 [11].…”

Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage

“…Ubiquitin specific peptidase 11 (USP11) is a member of the ubiquitin-specific proteases (USPs) family of deubiquitinase enzymes [ 29 ]. USP11 participates in various signaling pathways and biological processes such as TGFβ signaling, pro-inflammatory signaling, viral replication, and NF-κB signaling, by regulating deubiquitination and protein stability of various targets such as TβRII, ALK5, LPA1, NP protein, and IκBα [ 30 - 34 ]. Additionally, USP11 has emerged to positively regulate DNA double-strand break (DSB) repair by regulating PALB2 deubiquitination, by modifying recruitment of RAD51 and 53BP1 to the DNA damage site dependent on its catalytic activity, and by interacting with BRCA2 independent of its catalytic activity [ 35 - 38 ].…”

DUBbing Down Translation: The Functional Interaction of Deubiquitinases with the Translational Machinery

“…However, the impact of methylation on the USP11-driven protein translational machinery is unclear at present (43). Apart from eIF4B, USP11 also stabilizes multiple other proteins, such as RAE1 (44), ALK5 (45), BRCA2 (46), and TGFb receptor II (47) and thus plays vital roles in regulating proliferative TGFb signaling, DNA double-strand repair, and chromatin segregation, positioning USP11 as an attractive therapeutic target.…”