TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination

J Biol Chem. 2012 Aug 17;287(34):28646-55. doi: 10.1074/jbc.M112.362608. Epub 2012 Jun 28.

Abstract

Viral infection activates several transcription factors including NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. MITA (also called STING) is a critical adaptor protein that links virus-sensing receptors to IRF3 activation upon infection by both RNA and DNA pathogens. Here we show that the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) ubiquitinated MITA and dramatically enhanced MITA-mediated induction of IFN-β. Overexpression of TRIM32 potentiated virus-triggered IFNB1 expression and cellular antiviral response. Consistently, knockdown of TRIM32 had opposite effects. TRIM32 interacted with MITA, and was located at the mitochondria and endoplasmic reticulum. TRIM32 targeted MITA for K63-linked ubiquitination at K20/150/224/236 through its E3 ubiquitin ligase activity, which promoted the interaction of MITA with TBK1. These findings suggest that TRIM32 is an important regulatory protein for innate immunity against both RNA and DNA viruses by targeting MITA for K63-linked ubiquitination and downstream activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA Viruses / genetics
  • DNA Viruses / metabolism
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Viruses / genetics
  • RNA Viruses / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases
  • Ubiquitination*

Substances

  • Membrane Proteins
  • Mitochondrial Proteins
  • STING1 protein, human
  • Transcription Factors
  • Tripartite Motif Proteins
  • Interferon-beta
  • TRIM32 protein, human
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human