title: The ubiquitin E3 ligase RAUL negatively regulates type i interferon through ubiquitination of the transcription factors IRF7 and IRF3.
abstract: 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.
authors.affiliation: Viral Oncology Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 3M09, Baltimore, MD 21231, USA. yyanxin1@jhmi.edu
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Yu
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hayward
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C555759:UBE3C protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex