Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6

J Biol Chem. 2010 Feb 12;285(7):4291-7. doi: 10.1074/jbc.M109.074971. Epub 2009 Dec 7.

Abstract

Ubiquitination and deubiquitination have emerged as critical post-translational regulatory mechanisms for activation or attenuation of the virus-triggered type I interferon (IFN)(2) induction pathways. In this study, we identified two deubiquitinating enzymes, OTUB1 and OTUB2, as negative regulators of virus-triggered type I IFN induction. Overexpression of OTUB1 and OTUB2 inhibited virus-induced activation of IRF3 and NF-kappaB, transcription of the IFNB1 gene as well as cellular antiviral response, whereas knockdown of OTUB1 and OTUB2 had opposite effects. Coimmunoprecipitations indicated OTUB1 and -2 interacted with TRAF3 and TRAF6, two E3 ubiquitin ligases required for virus-triggered IRF3 and NF-kappaB activation, respectively. Furthermore, we found that OTUB1 and OTUB2 mediated virus-triggered deubiquitination of TRAF3 and -6. These findings suggest that OTUB1 and OTUB2 negatively regulate virus-triggered type I IFN induction and cellular antiviral response by deubiquitinating TRAF3 and -6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / metabolism
  • NF-kappa B / metabolism
  • Protein Binding
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sendai virus / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / metabolism*
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism*
  • Ubiquitination / genetics
  • Ubiquitination / physiology

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • NF-kappa B
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 6
  • OTUB2 protein, human
  • Thiolester Hydrolases
  • OTUB1 protein, human
  • Cysteine Endopeptidases