Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3

Cell. 2005 Sep 9;122(5):669-82. doi: 10.1016/j.cell.2005.08.012.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Bacterial / genetics
  • Gene Silencing
  • HeLa Cells
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon-beta / immunology
  • Interferons / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / physiology*
  • Mitochondria / immunology*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / immunology
  • Mitochondrial Proteins / physiology*
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / immunology
  • RNA, Double-Stranded / immunology
  • Respirovirus Infections / immunology
  • Respirovirus Infections / virology
  • Sendai virus / genetics
  • Sendai virus / immunology
  • Sequence Alignment
  • Signal Transduction / immunology*
  • Transcription Factors / metabolism*
  • Virus Replication / immunology

Substances

  • DNA-Binding Proteins
  • IRF3 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Membrane Proteins
  • Mitochondrial Proteins
  • NF-kappa B
  • RNA, Double-Stranded
  • Transcription Factors
  • Interferon-beta
  • Interferons
  • Protein-Serine-Threonine Kinases

Associated data

  • GENBANK/BC044952
  • GENBANK/DQ174270
  • GENBANK/DQ174271