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OTUB1 modulates c-IAP1 stability to regulate signalling pathways

Tatiana Goncharov1, Kyle Niessen, Maria Cristina de Almagro

  • 1Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 94080, USA.

The EMBO Journal
|March 26, 2013
PubMed

Insights

OTUB1 deubiquitinates c-IAP1, regulating TNF receptor signaling. OTUB1 downregulation enhances cell death and disrupts NF-κB/MAPK pathways, impacting gene expression and zebrafish vasculature.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Cellular inhibitor of apoptosis (c-IAP) proteins are E3 ubiquitin ligases crucial for TNF receptor (TNFR)-mediated signaling.
  • c-IAPs regulate TNFR signaling complexes by ubiquitylating key proteins like RIP1 and NIK.
  • Loss of c-IAPs severely impairs TNFR-induced NF-κB and MAPK pathway activation and gene expression.

Purpose of the Study:

  • To identify deubiquitinating enzymes associated with c-IAPs.
  • To elucidate the role of OTUB1 in regulating c-IAP1 stability and function.
  • To investigate the impact of OTUB1 on TNFR-mediated signaling pathways and cell death.

Main Methods:

  • In vitro and in vivo assays to assess OTUB1's deubiquitinating activity on c-IAP1.
  • TWEAK receptor signaling complex analysis.
  • Cellular assays to measure caspase activation, cell death, and protein degradation.
  • Knockdown studies in cell lines and zebrafish to evaluate pathway activation and physiological effects.

Main Results:

  • OTUB1 was identified as a c-IAP-associated deubiquitinating enzyme that specifically removes K48-linked polyubiquitin chains from c-IAP1.
  • OTUB1 downregulation promotes TWEAK- and IAP antagonist-induced caspase activation, cell death, and c-IAP1 degradation.
  • OTUB1 knockdown reduces TWEAK-induced NF-κB and MAPK pathway activation and alters TWEAK-mediated gene expression.
  • Suppression of OTUB1 in zebrafish destabilizes c-IAP levels and disrupts vasculature.

Conclusions:

  • OTUB1 regulates c-IAP1 stability through deubiquitination.
  • OTUB1 plays a critical role in modulating TNF-dependent cell death and NF-κB/MAPK signaling pathways.
  • OTUB1 is a key regulator of TNFR signaling, impacting cellular processes and organismal development.

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