TGFBR2 is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells. Issue 7 (16th May 2022)

• Record Type: Journal Article
• Authors: Yang, Liu; Wang, Siqi; Pan, Zengxiang; Du, Xing; Li, Qifa
• Is Part Of: Journal of cellular physiology. Volume 237:Issue 7(2022)
• Page Start: 2969
• Page End: 2979
• Publication Date: 2022-05-16
• Subjects: deubiquitination -- granulosa cell apoptosis -- TGFBR2 -- TGF‐β signaling pathway -- USP9X; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30776
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: The ubiquitin‐specific peptidase 9 X‐linked (USP9X) is one of the highly conserved members belonging to the ubiquitin‐specific proteases (USPs) family, which has been reported to control substrates‐mediated biological functions through deubiquitinating and stabilizing substrates. Here, we have found that TGFBR2, the type II receptor of the transforming growth factor beta (TGF‐β) signaling pathway, is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells (GCs). Mechanically, USP9X positively influences the expression of TGFBR2 at different levels through two independent ways: (i) directly targets and deubiquitinates TGFBR2, which maintains the protein stability of TGFBR2 through avoiding degradation mediated by ubiquitin‐proteasome system; (ii) indirectly maintains TGFBR2 messenger RNA (mRNA) expression via SMAD4/miR‐143 axis. Specifically, SMAD4, another substrate of USP9X, acts as a transcription factor and suppresses miR‐143 which inhibits the mRNA level of TGFBR2 by directly binding to its 3′‐untranslated region. Functionally, the maintenance of TGFBR2 by USP9X activates the TGF‐β signaling pathway, which further represses GC apoptosis. Our study highlights a functional micro‐regulatory network composed of deubiquitinase (USP9X), small noncoding RNA (miR‐143) and the TGF‐β signaling pathway, which plays a crucial role in the regulation of GC apoptosis and female fertility. Abstract : Here, we have found that TGFBR2, the type II receptor of the transforming growth factor‐β signaling pathway, is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells (GCs).