USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7

The amplitude of transforming growth factor-beta (TGF-beta) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF-beta signaling acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF-beta 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-beta 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-beta receptor stabilization and enhanced levels of p-SMAD2. Clinically, loss of USP26 correlates with high TGF-beta activity and confers poor prognosis in glioblastoma. Our data identify USP26 as a novel negative regulator of the TGF-beta pathway and suggest that loss of USP26 expression may be an important factor in glioblastoma pathogenesis.