Das T et al. (2021), The Multifaceted Roles of USP15 in Signal Trans...

XB-ART-58159

Int J Mol Sci 2021 Apr 29;229:. doi: 10.3390/ijms22094728.

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The Multifaceted Roles of USP15 in Signal Transduction.

Das T , Song EJ , Kim EE .

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Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.

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Species referenced: Xenopus laevis
Genes referenced: mdm2 smad4 smad6.2 smad7 smurf1 smurf2 tp53 usp15

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	Figure 1. USP15 in the regulation of TGF-β and BMP signaling. (a) USP15 binds to SMAD7 and opposes SMURF2-mediated ubiquitination of TβRI. The deubiquitination and stabilization of TβRI by USP15 promotes TGF-β activity and triggers the downstream gene expression to stimulate cell proliferation, migration wound healing, and glioblastoma pathogenesis [13]. (b) Upon activation by BMP ligands, the receptor-regulated R-SMADs undergo phosphorylation, bind to SMAD4, and enter the nucleus to induce target gene transcription. SMAD6 is a negative regulator that competes with SMAD4 to bind to R-SMADs and induces SMURF1-mediated ubiquitination and degradation of R-SMADs. Through its interaction with SMAD6, USP15 deubiquitinates and stabilizes BMPR1 and R-SMADs to enhance the BMP signaling and elicit target gene expression [39]
	Figure 2. USP15 suppresses TNFα and Wnt signaling in association with CSN. Upon stimulation by TNFα, NF-ĸB is activated through phosphorylation and ubiquitin-dependent degradation of IĸB by CRL/SCFβTrCP E3 ubiquitin ligase to turn on its downstream target genes. USP15, in association with CSN, deubiquitinates and promotes IĸB stabilization by inhibiting CRL/SCFβTrCP activity and hinders NF-ĸB signaling (left) [33]. USP15 negatively regulates Wnt/β-catenin signaling by promoting the formation of the β-catenin destruction complex. In association with CSN, USP15 deubiquitinates and induces the stability of the essential component of the β-catenin destruction complex APC, which is required to target the phosphorylated β-catenin for CRLβ-TrCP-dependent proteasomal degradation (right) [35].
	Figure 3. Regulation of p53 signaling by USP15. USP15 translation is upregulated by TGF-β through the PI3K/AKT pathway, which in turn increases the stabilization of p53 by its deubiquitination and activates p53 signaling. In another way, USP15 also promotes the ubiquitin-dependent degradation of p53 by deubiquitination and enhanced stabilization of the E3 ubiquitin ligase for p53, MDM2, resulting in the downregulation of p53 target gene expression [34,84].

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Akhurst, TGF-beta signaling in cancer--a double-edged sword. 2001, Pubmed