The ubiquitin E3 ligase RAUL negatively regulates type i interferon through ubiquitination of the transcription factors IRF7 and IRF3

Immunity. 2010 Dec 14;33(6):863-77. doi: 10.1016/j.immuni.2010.11.027.


In the course of combating infectious agents, type I interferon (IFN) needs a timely downregulation mechanism to avoid detrimental overreaction. Here we showed a mechanism for restraining type I IFN responses, which relied on a HECT domain ubiquitin (Ub) E3 ligase, RAUL. RAUL limited type I IFN production by directly catalyzing lysine 48-linked polyubiquitination of both interferon regulatory factor 7 (IRF7) and IRF3 followed by proteasome-dependent degradation. Suppression of RAUL by dominant-negative RAUL or siRNA augmented both basal and virus-induced production of type I IFN, which resulted in reduced viral replication. The Kaposi's sarcoma-associated herpes virus immediate-early lytic cycle trigger protein RTA recruited this mechanism to augment its countermeasures against the host antiviral response. These results unveil a previously unrecognized "brake mechanism" for type I IFN that maintains proper low amounts of type I IFN under physiological conditions and restrains its magnitude when the antiviral response intensifies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Down-Regulation / genetics
  • Fibroblasts / immunology
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibroblasts / virology
  • Herpesviridae Infections / genetics
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / metabolism
  • Herpesvirus 8, Human / pathogenicity
  • Herpesvirus 8, Human / physiology*
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Mice
  • Mutant Proteins / genetics
  • Proteasome Endopeptidase Complex
  • RNA, Small Interfering / genetics
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / genetics
  • Virus Replication / genetics


  • IRF3 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Mutant Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • UBE3C protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex