IMMUNOLOGY Antiviral Signaling from the Mitochondria

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-B, 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-B, 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-B 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]