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

Lina Herhaus, Mazin Al-Salihi, Thomas Macartney, Simone Weidlich and Gopal P. Sapkota ()
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Lina Herhaus: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee
Mazin Al-Salihi: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee
Thomas Macartney: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee
Simone Weidlich: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee
Gopal P. Sapkota: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract SMAD transcription factors are key intracellular transducers of TGFβ cytokines. SMADs are tightly regulated to ensure balanced cellular responses to TGFβ 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 TGFβ induction. Further, OTUB1 has a crucial role in TGFβ-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 TGFβ-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 TGFβ pathway.

Date: 2013
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DOI: 10.1038/ncomms3519

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