USP 26 regulates TGF ‐β signaling by deubiquitinating and stabilizing SMAD 7

Abstract

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 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‐β receptor stabilization and enhanced levels of p‐SMAD2. Clinically, loss of USP26 correlates with high TGF‐β activity and confers poor prognosis in glioblastoma. Our data identify USP26 as a novel negative regulator of the TGF‐β pathway and suggest that loss of USP26 expression may be an important factor in glioblastoma pathogenesis.

Response to: USP26 regulates TGF‐β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma

“…In line with our previous results, we demonstrate that low USP26 expression is associated with poorer overall survival in glioblastoma, at the median threshold (high vs low), showing statistical significance with an overall P-value of 0.0259 (REMBRANDT) (new [3]). In line with our previous results, we demonstrate that low USP26 expression is associated with poorer overall survival in glioblastoma, at the median threshold (high vs low), showing statistical significance with an overall P-value of 0.0259 (REMBRANDT) (new [3]).…”

“…While our new analysis of the REMBRANDT database does not show a correlation between lower patient survival and high TGFBRI, TGFBRII, or TGFBRIII expression at the median threshold (new Fig EV5B-D in Kit Lend Lui et al [3]), our additional analysis of the TCGA (cBioPortal) dataset would suggest a correlation for TGFBRII, as claimed in our paper (high versus low; Fig 2C). As noted, we did not realise that the REMBRANDT dataset was comprised of glioblastoma and lower-grade gliomas.…”

“…decreased overall survival at the median threshold (high versus low, P = 0.039; new Fig EV5E in Kit Lend Lui et al[3]). Taken together, these data are consistent with our original conclusions that deregulation of TGFb pathway components, resulting in the hyperactivation of the TGF-b pathway, may act as biomarkers for poor clinical outcome in glioblastoma.…”

USP26 regulates TGF‐β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma

“…Extensive research into TGF-b signalling gives rise to many clinical trials, and among them over 20 are for cancer treatment [1]. In an attempt to show clinical significance, Kit Leng Lui et al [2] further suggest that the loss of USP26 correlates with high TGF-b activity and poorer patient survival/prognosis in glioblastoma. A paper by Kit Leng Lui et al [2] reports the involvement of the deubiquitinating enzyme USP26 as a key modulator of TGF-b activity through stabilisation of the negative feedback inhibitor Smad7.…”

Smad7 as a Target for Immunomodulation Strategy in Inflammatory Bowel Diseases

“…Studies in cancer cells have also shown that Smad7 levels are controlled by USP26, a deubiquitinating enzyme, which preventes Smad7 degradation [29]. On the other hand, there are intracellular mechanisms that counteract Smad7 activity.…”