Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Bacterial / genetics
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Gene Silencing
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HeLa Cells
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Humans
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Immunity, Innate*
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Interferon-beta / immunology
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Interferons / immunology
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / physiology*
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Mitochondria / immunology*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / immunology
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Mitochondrial Proteins / physiology*
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Molecular Sequence Data
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NF-kappa B / metabolism*
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Protein Serine-Threonine Kinases / immunology
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RNA, Double-Stranded / immunology
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Respirovirus Infections / immunology
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Respirovirus Infections / virology
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Sendai virus / genetics
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Sendai virus / immunology
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Sequence Alignment
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Signal Transduction / immunology*
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Transcription Factors / metabolism*
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Virus Replication / immunology
Substances
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DNA-Binding Proteins
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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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Membrane Proteins
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Mitochondrial Proteins
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NF-kappa B
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RNA, Double-Stranded
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Transcription Factors
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Interferon-beta
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Interferons
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Protein Serine-Threonine Kinases
Associated data
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GENBANK/BC044952
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GENBANK/DQ174270
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GENBANK/DQ174271