Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification

Mol Cell Biol. 2010 May;30(10):2424-36. doi: 10.1128/MCB.01466-09. Epub 2010 Mar 22.

Abstract

Virus infection induces host antiviral responses, including induction of type I interferons. Transcription factor interferon regulatory factor 3 (IRF3) plays a pivotal role and is tightly regulated in this process. Here, we identify HERC5 (HECT domain and RLD 5) as a specific binding protein of IRF3 by immunoprecipitation. Ectopic expression or knockdown of HERC5 could, respectively, enhance or impair IRF3-mediated gene expression. Mechanistically, HERC5 catalyzes the conjugation of ubiquitin-like protein ISG15 onto IRF3 (Lys193, -360, and -366), thus attenuating the interaction between Pin1 and IRF3, resulting in sustained IRF3 activation. In contrast to results for wild-type IRF3, the mutant IRF3(K193,360,366R) interacts tightly with Pin1, is highly polyubiquitinated, and becomes less stable upon Sendai virus (SeV) infection. Consistently, host antiviral responses are obviously boosted or crippled in the presence or absence of HERC5, respectively. Collectively, this study characterizes HERC5 as a positive regulator of innate antiviral responses. It sustains IRF3 activation via a novel posttranslational modification, ISGylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Immunity, Innate / physiology
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Protein Binding
  • Protein Processing, Post-Translational
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Ubiquitin / metabolism
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*

Substances

  • Cytokines
  • HERC5 protein, human
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • Ubiquitin
  • Ubiquitins
  • ISG15 protein, human