USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination

作者：Iyengar Prasanna Vasudevan; Jaynes Patrick; Rodon Laura; Lama Dilraj; Law Kai Pong; Lim Yoon Pin; Verma Chandra; Seoane Joan; Eichhorn Pieter Johan Adam^*

来源：Scientific Reports, 2015, 5(1): 14733.

DOI：10.1038/srep14733

Ubiquitin modification of the TGF-beta pathway components is emerging as a key mechanism of TGF-beta pathway regulation. To limit TGF-beta responses, TGF-beta signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-beta receptor (T beta R) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the T beta R. However the precise mechanism by which these DUBs act on T beta R function remains poorly defined. Here, we demonstrate that apart from targeting the T beta R complex directly, USP15 also deubiquitinates SMURF2 resulting in enhanced T beta R stability and downstream pathway activation. Through proteomic analysis, we show that USP15 modulates the ubiquitination of Lys734, a residue required for SMURF2 catalytic activity. Our results show that SMURF2 is a critical target of USP15 in the TGF-beta pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways.

• 出版日期2015-10-5
• 单位南阳理工学院