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

Cell 122:669-682, 2005

Speaker: 羅苑菁                            Time: 2005/11/30 15:10~16:00

Commentator: 凌 斌  老師                   Place: Room 601

Abstract:

The innate immune response is a first line of defense against viral pathogens .An integral component of innate antiviral defense is the production of type 1 interferons (IFN) including INF-α and INF-β.Genes encoding type 1 interferons must first be transcriptionally induced in viral infected cells. What is the viral sensor in the body？Yoneyama et al. report that a cytoplasmic RNA helicase called RIG-1 is essential component of the detection system. RIG-1 has an N-terminal CARD domain which mediates IFN-β activation, and a C-terminal helicase domain recognizing viral RNPs. Until now the RIG-1 pathway is still not understood, the authors want to clarify the RIG-1 signaling pathway. First, they try to identify proteins containing CARD-like domains similar to those of RIG-1 and a protein called KIAA1271 is found. The authors name the protein as MAVS (mitochondrial antiviral signaling protein). MAVS contains an N-terminal CARD-like domain, a praline-rich region and a C-terminal transmembrane domain. Second, MAVS can induce IFN-β, NF-κB and IRF3 activation in response to viruses. Because MAVS can induce interferons, the author examine this protein could mediate immune defense against viruses. The results shows that HEK 293 cells expressed MAVS are not killed by the virus and the virus titer is twenty fold lower than control HEK293 cells. Then epistatsis experiments show that MAVS functions downstream of RIG-1 and upstream of TBK1 and IKKε. Finally, Both N-terminal CARD domain and C-terminal transmembrane domain of MAVS are necessary for MAVS antiviral signaling. Unexpectedly the transmembrane domain is targeting to mitochondria. This is the first time to connect mitochondria and innate immunity. Conclusion, the authors find out a novel cellular protein located on the mitochondrial membrane to mediate innate immunity against viral infection.

Reference:

1.      Levy, D.E.& Marie, I.J. RIGging an antiviral defense-it’s in the CARDs. Nat.Immunol. 5: 699-701, 2004

2.      Yoneyama et al. The RNA helicase RIG-1 has an essential function in double-stranded RNA-induced innate antiviral response.Nat.Immunol.22: 730-736, 2004