A Mitochondrial Antivirus Defense

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Science  23 Sep 2005:
Vol. 309, Issue 5743, pp. 1969
DOI: 10.1126/science.309.5743.1969b

Intracellular viral double-stranded RNA (dsRNA) is detected by the protein RIG-1, which has a C-terminal domain that binds dsRNA. RIG-1 stimulates the coordinated activation of multiple transcription factors, including NF-κB, IRF3, and ATF2, which together act to regulate the expression of type 1 interferons, such as interferon-β (IFN-β), and thus promote the response to viral infection. Seth et al. have investigated the role of a protein named MAVS (for mitochondrial antiviral signaling) in mediating the downstream effects of RIG-1. Overexpression of MAVS in HEK293 cells activated IRF-3, NF-κB, and JNK (which activates ATF-2) and increased the abundance of endogenous IFN-β. Silencing MAVS abolished expression of IFN-βin response to Sendai virus. Moreover, MAVS overexpression protected cells from vesicular stomatitis virus-mediated death, whereas MAVS silencing sensitized the cells. Confocal microscopy and subcellular fractionation indicated that MAVS localized to the mitochondria, and localization depended on the transmembrane domain: Replacing this sequence with analogous domains from mitochondrial membrane proteins (Bcl-xL or Bcl-2) preserved MAVS activity, whereas targeting to other membranes reduced it. Thus, MAVS provides an unexpected link between mitochondria and the immune response. Two other groups, Xu et al. and Kawai et al., have identified this same protein as an adapter that acts downstream of RIG-1 to stimulate IFN-β expression. — EMA

Cell 122, 669 (2005); Mol. Cell. 10.1016/j.molcel.2005.08.014 (2005); Nat. Immunol. 10.1038/ni1243 (2005).

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