Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.
Viral infection triggers host innate immune responses through activation of the transcription factors NF-kappaB and IRF 3, which coordinately regulate the expression of type-I interferons such as interferon-beta (IFN-beta). Herein, we report the identification of a novel protein termed MAVS (mitochondrial antiviral signaling), which mediates the activation of NF-kappaB and IRF 3 in response to viral infection. Silencing of MAVS expression through RNA interference abolishes the activation of NF-kappaB and IRF 3 by viruses, thereby permitting viral replication. Conversely, overexpression of MAVS induces the expression of IFN-beta through activation of NF-kappaB and IRF 3, thus boosting antiviral immunity. Epistasis experiments show that MAVS is required for the phosphorylation of IRF 3 and IkappaB and functions downstream of RIG-I, an intracellular receptor for viral RNA. MAVS contains an N-terminal CARD-like domain and a C-terminal transmembrane domain, both of which are essential for MAVS signaling. The transmembrane domain targets MAVS to the mitochondria, implicating a new role of mitochondria in innate immunity.
Seth
Rashu B
RB
Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Sun
Lijun
L
Ea
Chee-Kwee
CK
Chen
Zhijian J
ZJ
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016899:Interferon-beta / Q000276:immunology; D007372:Interferons / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008928:Mitochondria / Q000276:immunology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology; D010253:Respirovirus Infections / Q000276:immunology / Q000821:virology; D029082:Sendai virus / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication / Q000276:immunology
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D014157:Transcription Factors; D016899:Interferon-beta; D007372:Interferons; D017346:Protein Serine-Threonine Kinases