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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Down-Regulation / genetics
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Fibroblasts / immunology
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Fibroblasts / virology
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Herpesviridae Infections / genetics
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Herpesviridae Infections / immunology*
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Herpesviridae Infections / metabolism
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Herpesvirus 8, Human / pathogenicity
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Herpesvirus 8, Human / physiology*
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Humans
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Interferon Regulatory Factor-3 / metabolism
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Interferon Regulatory Factor-7 / metabolism
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Interferon Type I / genetics
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Interferon Type I / immunology
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Interferon Type I / metabolism*
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Mice
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Mutant Proteins / genetics
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Proteasome Endopeptidase Complex
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RNA, Small Interfering / genetics
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Transcription Factors / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / immunology
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination / genetics
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Virus Replication / genetics
Substances
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IRF3 protein, human
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IRF7 protein, human
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Interferon Type I
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Mutant Proteins
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RNA, Small Interfering
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Transcription Factors
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UBE3C protein, human
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Ubiquitin-Protein Ligases
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Proteasome Endopeptidase Complex