The Specific and Essential Role of MAVS in Antiviral Innate Immune Responses

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Immunity (Impact Factor: 19.75). 06/2006; 24(5):633-42. DOI: 10.1016/j.immuni.2006.04.004
Source: PubMed

ABSTRACT The mitochondrial antiviral signaling protein (MAVS) mediates the activation of NFkappaB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by cytosolic DNA, but the in vivo evidence is lacking. By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFkappaB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs). However, MAVS was not required for interferon induction by cytosolic DNA or by Listeria monocytogenes. Mice lacking MAVS were viable and fertile, but they failed to induce interferons in response to poly(I:C) stimulation and were severely compromised in immune defense against viral infection. These results provide the in vivo evidence that the cytosolic viral signaling pathway through MAVS is specifically required for innate immune responses against viral infection.

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    ABSTRACT: The mitochondrial antiviral signaling protein (MAVS) plays a key role in the signal transduction of RIG-I-like receptors (RLRs)-mediated antiviral response. In the present study, zebrafish MAVS transcript variants, namely MAVS_tv1 and MAVS_tv2, were cloned from zebrafish embryos. The putative MAVS_tv1 protein (full length form) contains an N-terminal CARD domain, a central proline region, and a C-terminal transmembrane domain (TM). MAVS_tv2 is generated by a 190 bp intron fragment insertion. The putative MAVS_tv2 protein lacked TM domain due to a frame shift, with the N-terminal 303 aa residues identical to MAVS_tv1, and no sequence homology for the C-terminal 41 aa residues. Real-time PCR showed that the expression of MAVS_tv1 in ZF4 cells was higher than that of MAVS_tv2, and MAVS variants were induced by Edwardsiella tarda and SVCV infection during the early time points of infection, whereas MAVS_tv1 unchanged or MAVS_tv2 decreased at a later time point after the infection, respectively. Overexpression of MAVS_tv1 and MAVS_tv2 in fish cells conferred antiviral resistance, and activated zebrafish IFN1 and IFN3 promoters. MAVS_tv1 overexpression induced a slow (48 hpf) increased expression of IFN1, mxa, mxb, mxe and RSAD2. In contrast, MAVS_tv2 overexpression increased rapidly and transiently the expression of IFN1, IFN2, IFN3, mxc and rsad2 at 6 or 24 hpf. The simultaneous overexpression of MAVS variants and RIG-I in zebrafish embryos led to an accumulative induction of IFNs and IFN-stimulated genes including IFN1, IFN4, mxc, mxe and rsad. Furthermore, MAVS_tv1 cooperated with RIG-I in the accumulation of RIG-I transcript in a positive feedback loop; MAVS_tv2 synergized with MDA5 in the accumulation of MAVS_tv2 transcript. Collectively, these data suggest the molecular mechanisms of fish MAVS variants in antiviral immunity.
    Developmental & Comparative Immunology 11/2014; DOI:10.1016/j.dci.2014.10.017 · 3.71 Impact Factor
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    ABSTRACT: Mitochondria are cellular organelles involved in host-cell metabolic processes and the control of programmed cell death. A direct link between mitochondria and innate immune signalling was first highlighted with the identification of MAVS-a crucial adaptor for RIGI-like receptor signalling-as a mitochondria-anchored protein. Recently, other innate immune molecules, such as NLRX1, TRAF6, NLRP3 and IRGM have been functionally associated with mitochondria. Furthermore, mitochondrial alarmins-such as mitochondrial DNA and formyl peptides-can be released by damaged mitochondria and trigger inflammation. Therefore, mitochondria emerge as a fundamental hub for innate immune signalling.
    EMBO Reports 07/2011; 12(9):901-10. DOI:10.1038/embor.2011.157 · 7.86 Impact Factor


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