Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3

Viral infection triggers host innate immune responses through activation of the transcription factors NFB and IRF3, which coordinately regulate the expression of type-I interferons such as interferon(IFN). Herein, we report the identification of a novel protein termed MAVS (mitochondrial antiviral signaling), which mediates the activation of NFB and IRF3 in response to viral infection. Silencing of MAVS expression through RNA interference abolishes the activation of NFB and IRF3 by viruses, thereby permitting viral replication. Conversely, overexpression of MAVS induces the expression of IFNthrough activation of NFB and IRF3, thus boosting antiviral immunity. Epistasis experiments show that MAVS is required for the phosphorylation of IRF3 and I B 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.