OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3

Lina Herhaus, Mazin Al-Salihi, Thomas Macartney, Simone Weidlich, Gopal Sapkota (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    95 Citations (Scopus)


    SMAD transcription factors are key intracellular transducers of TGFß cytokines. SMADs are tightly regulated to ensure balanced cellular responses to TGFß signals. Ubiquitylation has a key role in regulating SMAD stability and activity. Several E3 ubiquitin ligases that regulate the turnover of SMADs are known; however, proteins that prevent the ubiquitylation or cause deubiquitylation of active SMADs remain undefined. Here we demonstrate that OTUB1 is recruited to the active phospho-SMAD2/3 complex only on TGFß induction. Further, OTUB1 has a crucial role in TGFß-mediated gene transcription and cellular migration. OTUB1 inhibits the ubiquitylation of phospho-SMAD2/3 by binding to and inhibiting the E2 ubiquitin-conjugating enzymes independent of its catalytic activity. Consequently, depletion of OTUB1 in cells causes a rapid loss in levels of TGFß-induced phospho-SMAD2/3, which is rescued by the proteasomal inhibitor bortezomib. Our findings uncover a signal-induced phosphorylation-dependent recruitment of OTUB1 to its target in the TGFß pathway.
    Original languageEnglish
    Article number2519
    JournalNature Communications
    Publication statusPublished - 27 Sept 2013


    • SMAD
    • OTUB1
    • DUB
    • TGF beta
    • Ubiquitin
    • Deubiquitinating enzyme
    • E2 ubiquitin-conjugating enzyme
    • E3 ligase

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)


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