Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6

Proc Natl Acad Sci U S A. 2015 Sep 8;112(36):11324-9. doi: 10.1073/pnas.1509968112. Epub 2015 Aug 24.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Embryo, Mammalian / cytology
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • Gene Expression / immunology
  • HEK293 Cells
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Immunoblotting
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Male
  • Mice, Knockout
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Proteasome Endopeptidase Complex / immunology
  • Proteasome Endopeptidase Complex / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • TNF Receptor-Associated Factor 3 / immunology*
  • TNF Receptor-Associated Factor 3 / metabolism
  • TNF Receptor-Associated Factor 6 / immunology*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / immunology*
  • Ubiquitin Thiolesterase / metabolism
  • Virus Diseases / genetics
  • Virus Diseases / immunology*
  • Virus Diseases / virology
  • Viruses / immunology*

Substances

  • Cytokines
  • Inflammation Mediators
  • Interferon Type I
  • NF-kappa B
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 6
  • USP25 protein, mouse
  • Ubiquitin Thiolesterase
  • Proteasome Endopeptidase Complex