Abstract
Host pathogen-recognition receptors detect nucleic acid from invading viruses and initiate a series of signaling pathways that lead to the production of type I interferons (IFNs) and proinflammatory cytokines. Here, we found that a viral infection-induced deubiquitinase (DUB), ubiquitin-specific protease 25 (USP25) was required for host defense against RNA and DNA viruses. The activation of transcription factors IRF3 and NF-κB was impaired and the production of type I IFNs and proinflammatory cytokines was inhibited in Usp25-/- cells compared with the wild-type counterparts after RNA or DNA viruses infection. Consistently, USP25 deficient mice were more susceptible to H5N1 or HSV-1 infection compared with the wild-type mice. USP25 was associated with TRAF3 and TRAF6 after infection by RNA or DNA viruses and protected virus-induced proteasome-dependent or independent degradation of TRAF3 and TRAF6, respectively. Moreover, reconstitution of TRAF3 and TRAF6 into Usp25-/- MEFs restored virus-triggered production of type I IFNs and proinflammatory cytokines. Our findings thus reveal a previously uncovered positive feedback regulation of innate immune responses against RNA and DNA viruses by USP25.
Keywords:
TRAF3; TRAF6; USP25; innate antiviral immunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Cytokines / genetics
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Cytokines / immunology
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Cytokines / metabolism
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Embryo, Mammalian / cytology
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Female
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Fibroblasts / immunology
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Fibroblasts / metabolism
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Fibroblasts / virology
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Gene Expression / immunology
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HEK293 Cells
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Host-Pathogen Interactions / immunology
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Humans
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Immunity, Innate / genetics
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Immunity, Innate / immunology*
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Immunoblotting
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Inflammation Mediators / immunology
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Inflammation Mediators / 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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Male
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Mice, Knockout
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NF-kappa B / immunology
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NF-kappa B / metabolism
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Proteasome Endopeptidase Complex / immunology
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Proteasome Endopeptidase Complex / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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TNF Receptor-Associated Factor 3 / immunology*
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TNF Receptor-Associated Factor 3 / metabolism
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TNF Receptor-Associated Factor 6 / immunology*
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TNF Receptor-Associated Factor 6 / metabolism
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / immunology*
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Ubiquitin Thiolesterase / metabolism
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Virus Diseases / genetics
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Virus Diseases / immunology*
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Virus Diseases / virology
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Viruses / immunology*
Substances
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Cytokines
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Inflammation Mediators
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Interferon Type I
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NF-kappa B
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TNF Receptor-Associated Factor 3
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TNF Receptor-Associated Factor 6
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USP25 protein, mouse
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Ubiquitin Thiolesterase
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Proteasome Endopeptidase Complex