Antiviral Signaling from the Mitochondria

Abstract

Intracellular viral double-stranded RNA (dsRNA) is detected by the protein RIG-1, which has a C-terminal domain that binds dsRNA and two N-terminal caspase recruitment domain (CARD) domains. RIG-1 stimulates the coordinated activation, through distinct pathways, of multiple transcription factors, including NF-κB, IRF3, and ATF2, which act together to regulate the expression of type-1 interferons, such as interferon-β (IFN-β), and thus promotes the response to viral infection (see McWhirter et al. ). CARD domains bind to other CARD domains; thus, Seth et al. investigated the possible role of a novel protein with an N-terminal CARD domain, which they 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); transcriptionally activated a luciferase reporter controlled by the IFN-β promoter; and increased the abundance of endogenous IFN-β. MAVS silencing with siRNA abolished expression of IFN-β in response to Sendai virus, poly(I:C) (which mimics viral dsRNA), or overexpression of the RIG-1 N-terminal fragment. Moreover, MAVS overexpression protected cells from vesicular stomatitis virus (VSV)-mediated death, whereas MAVS silencing sensitized the cells. Mutational analysis indicated that the MAVS CARD domain and a C-terminal transmembrane region were necessary and sufficient for MAVS signaling. Both confocal microscopy and fractionation indicated that MAVS localized to the mitochondria. Mitochondrial 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 appears to represent a novel protein that acts downstream of RIG-1 to coordinate the response to viral infection and to provide 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 acting downstream of RIG-1 to stimulate IFN-β expression. R. B. Seth, L. Sun, C.-K. Ea, Z. J. Chen, Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. Cell 122 , 669-682 (2005). [PubMed] L.-G. Xu, Y.-Y. Wang, K.-J. Han, L.-Y. Li, Z. Zhai, H.-B. Shu, VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell. Published online 8 September 2005 (doi: 10.1016/S109727650501556X). [Online Journal] T. Kawai, K. Takahashi, S. Sato, C. Coban, H. Kumar, H. Kato, K. J. Ishii, O. Takeuchi, S. Akira, IPS-1, an adaptor triggering RIG-1- and Mda5-mediated type 1 interferon induction. Nat. Immunol. Published online 28 August 2005 (doi: 10.1038/ni1243). [PubMed] S. M. McWhirter, B. R. tenOever, T. Maniatis, Connecting mitochondria and innate immunity. Cell 122 , 645-647 (2005). [PubMed]