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De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF

A-L Mahul-Mellier1, E Pazarentzos, C Datler

  • 1Imperial College London, Experimental Medicine and Toxicology, Hammersmith Campus, Du Cane Road, Burlington Danes Building, London W12 0NN, UK.

Cell Death and Differentiation
|December 20, 2011
PubMed

Insights

The ubiquitin-specific protease USP2a regulates TNFR1 complex signaling, controlling cell death decisions. USP2a de-ubiquitination of RIP1 and TRAF2 promotes cell survival by enabling NF-κB pathway reactivation.

Area of Science:

  • Cellular signaling pathways
  • Ubiquitination and de-ubiquitination
  • Apoptosis and cell survival regulation

Background:

  • Tumor Necrosis Factor Receptor 1 (TNFR1) complex signaling dictates cell fate.
  • Dynamic ubiquitination of TNFR1 complex components modulates signaling outcomes.
  • The precise role of de-ubiquitinating enzymes in TNFR1 complex regulation remains to be fully elucidated.

Purpose of the Study:

  • To investigate the role of ubiquitin-specific protease USP2a in TNFR1 complex-mediated cell death and survival decisions.
  • To identify novel components and regulatory mechanisms of the TNFR1 signaling pathway.

Main Methods:

  • Recruitment of USP2a to the TNFR1 complex upon ligand binding.
  • Analysis of USP2a's de-ubiquitinating activity on RIP1 and TRAF2.
  • Assessment of IκBα reappearance and NF-κB inactivation.
  • Evaluation of USP2a's impact on TNFR1 complex I to complex II conversion.

Main Results:

  • USP2a is a novel component of the TNFR1 complex.
  • USP2a removes K63-linked ubiquitin chains from RIP1 and TRAF2.
  • USP2a activity is essential for IκBα reappearance and NF-κB inactivation.
  • USP2a promotes the conversion of anti-apoptotic TNFR1 complex I to pro-apoptotic complex II.

Conclusions:

  • USP2a plays a critical role in determining cell fate downstream of TNFR1 signaling.
  • Downregulation of USP2a enhances NF-κB activation and confers resistance to TNF-induced cell death.
  • Targeting USP2a may offer a therapeutic strategy for modulating cell death pathways.

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