title: Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif.
abstract: Upon recognition of viral infection, RIG-I and Helicard recruit a newly identified adapter termed Cardif, which induces type I interferon (IFN)-mediated antiviral responses through an unknown mechanism. Here, we demonstrate that TRAF3, like Cardif, is required for type I interferon production in response to intracellular double-stranded RNA. Cardif-mediated IFNalpha induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif. Interestingly, while the entire N-terminus of TRAF3 was functionally interchangeable with that of TRAF5, the TRAF domain of TRAF3 was not. Our data suggest that this distinction is due to an inability of the TRAF domain of TRAF5 to bind the TIM of Cardif. Finally, we show that preventing association of TRAF3 with this TIM by mutating two critical amino acids in the TRAF domain also abolishes TRAF3-dependent IFN production following viral infection. Thus, our findings suggest that the direct and specific interaction between the TRAF domain of TRAF3 and the TIM of Cardif is required for optimal Cardif-mediated antiviral responses.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Supriya K
authors.initials: SK
authors.lastname: Saha
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pietras
authors.forename: Jeannie Q
authors.initials: JQ
authors.lastname: He
authors.forename: Jason R
authors.initials: JR
authors.lastname: Kang
authors.forename: Su-Yang
authors.initials: SY
authors.lastname: Liu
authors.forename: Gagik
authors.initials: G
authors.lastname: Oganesyan
authors.forename: Arash
authors.initials: A
authors.lastname: Shahangian
authors.forename: Brian
authors.initials: B
authors.lastname: Zarnegar
authors.forename: Travis L
authors.initials: TL
authors.lastname: Shiba
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000502:physiology; D051379:Mice; D012330:RNA, Double-Stranded / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D029082:Sendai virus / Q000235:genetics / Q000502:physiology; D048008:TNF Receptor-Associated Factor 3; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016898:Interferon-alpha; C505371:MAVS protein, human; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins