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USP26 regulates TGF-? signaling by deubiquitinating and stabilizing SMAD7.

ABSTRACT: The amplitude of transforming growth factor-? (TGF-?) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF-? signaling acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF-? receptor complex for ubiquitin-mediated degradation. Here, we identify the deubiquitinating enzyme USP26 as a novel integral component of this negative feedback loop. We demonstrate that TGF-? rapidly enhances the expression of USP26 and reinforces SMAD7 stability by limiting the ubiquitin-mediated turnover of SMAD7. Conversely, knockdown of USP26 rapidly degrades SMAD7 resulting in TGF-? receptor stabilization and enhanced levels of p-SMAD2. Clinically, loss of USP26 correlates with high TGF-? activity and confers poor prognosis in glioblastoma. Our data identify USP26 as a novel negative regulator of the TGF-? pathway and suggest that loss of USP26 expression may be an important factor in glioblastoma pathogenesis.

SUBMITTER: Kit Leng Lui S

PROVIDER: S-EPMC5412796 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7.

Kit Leng Lui Sarah S Iyengar Prasanna Vasudevan PV Jaynes Patrick P Isa Zul Fazreen Bin Adam ZFBA Pang Brendan B Tan Tuan Zea TZ Eichhorn Pieter Johan Adam PJA

EMBO reports 20170405 5

The amplitude of transforming growth factor-β (TGF-β) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF-β signaling acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF-β receptor complex for ubiquitin-mediated degradation. Here, we identify the deubiquitinating enzyme USP26 as a novel integral component of this negative feedback loop. We demonstrate that TGF-β rapi ...[more]

PMID: 28381482

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Project description:BackgroundTranscription factors YAP and TAZ function as the primary mediators of the Hippo pathway. Yet, crosstalk of YAP and TAZ with other signaling pathways remains relatively unexplored. We have explored the impact of YAP and TAZ levels on the TGF-β/Smad signaling pathway in human skin dermal fibroblasts.MethodsYAP and TAZ levels in dermal fibroblasts were reduced in dermal fibroblasts by siRNA-mediated knockdown. The effects of YAP and TAZ reduction on TGF-β/Smad signaling were examined by quantitative real-time PCR, Western analysis, and immunostaining. Luciferase reporter assays and electrophoretic mobility shift assays were conducted to investigate the transcription factor DNA-binding and transcriptional activities.ResultsKnockdown of both YAP and TAZ (YAP/TAZ), but not either separately, impaired TGF-β1-induced Smad3 phosphorylation and Smad3 transcriptional activity, thereby inhibiting the expression of TGF-β target genes. This reduction by reduced levels of YAP/TAZ results from induction of inhibitory Smad7, which inhibits Smad3 phosphorylation and activity by TGF-β1. Conversely, prevention of Smad7 induction restores Smad3 phosphorylation and Smad3 transcriptional activity in fibroblasts that have reduced YAP/TAZ. In agreement with these findings, inhibition of YAP/TAZ transcriptional activity, similar to the reduction of YAP/TAZ levels, also significantly induced Smad7 and impaired TGF-β/Smad signaling. Further investigations revealed that reduced levels of YAP/TAZ led to induction of activator protein-1 (AP-1) activity, Activated AP-1 bound to DNA sequences in the Smad7 gene promoter, and deletion of these AP-1 binding sequences substantially reduced Smad7 promoter reporter activity.ConclusionYAP/TAZ functions in concert with transcription factor AP-1 and Smad7 to regulate TGF-β signaling, in human dermal fibroblasts. Reduction of YAP/TAZ levels leads to activation of AP-1 activity, which induces Smad7. Smad7 suppresses the TGF-β pathway.

Dataset Information

USP26 regulates TGF-? signaling by deubiquitinating and stabilizing SMAD7.

Publications

USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7.

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