E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1

Nat Immunol. 2016 Dec;17(12):1342-1351. doi: 10.1038/ni.3588. Epub 2016 Oct 24.

Abstract

TBK1 is essential for interferon-β (IFN-β) production and innate antiviral immunity. Here we identified the T cell anergy-related E3 ubiquitin ligase RNF128 as a positive regulator of TBK1 activation. RNF128 directly interacted with TBK1 through its protease-associated (PA) domain and catalyzed the K63-linked polyubiquitination of TBK1, which led to TBK1 activation, IRF3 activation and IFN-β production. Deficiency of RNF128 expression attenuated IRF3 activation, IFN-β production and innate antiviral immune responses to RNA and DNA viruses, in vitro and in vivo. Our study identified RNF128 as an E3 ligase for K63-linked ubiquitination and activation of TBK1 and delineated a previously unrecognized function for RNF128.

MeSH terms

  • Animals
  • Female
  • HEK293 Cells
  • Herpes Simplex / immunology*
  • Herpesvirus 1, Human / immunology*
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-beta / metabolism
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / genetics
  • Signal Transduction / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Vesicular Stomatitis / immunology*
  • Vesiculovirus / immunology*

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • RNA, Small Interfering
  • Interferon-beta
  • RNF128 protein, human
  • RNF128 protein, mouse
  • Ubiquitin-Protein Ligases
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases