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: 21.56). 06/2006; 24(5):633-42. DOI: 10.1016/j.immuni.2006.04.004
Source: PubMed


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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    • "Our previous studies show that two related variants of MDA5 and LGP2, two master regulators of antiviral innate immunity, are produced by alternative splicing, and the truncated variants MDA5b and LGP2b act as a regulator for antiviral signaling (Chang et al., 2011; Zou et al., 2014). MAVS has been shown to play a pivotal role in controlling viral infections (Kumar et al., 2006; Sun et al., 2006). In mammals, multiple MAVS variants are produced through differential mRNA splicing (MAVS 1a, 1b and 1c) or by alternative translation initiation from a single transcript (miniMAVS). "
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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; 49(1). DOI:10.1016/j.dci.2014.10.017 · 2.82 Impact Factor
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    • "Secreted L. monocytogenes DNA could also be detected using these RNA receptor systems if it is transcribed into RNA by host cell RNA polymerase III (37). However, deficiency in RIG-I, MDA5, or MAVS fails to ablate IFNβ production by L. monocytogenes-infected BMM (37, 44, 45). Thus, it does not appear that RNA sensing is crucial for recognizing cytosolic L. monocytogenes infection in this cell type, although it may play a more important role in sensing L. monocytogenes infection of other cell types and for sensing infection by other bacteria, namely Legionella pneumophila (46, 47). "
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    ABSTRACT: Type I interferons (IFNs) were first described for their ability to protect the host from viral infections and may also have beneficial effects under specific conditions within some bacterial infections. Yet, these pleiotropic cytokines are now known to exacerbate infections by numerous life-threatening bacteria, including the intracellular pathogens Listeria monocytogenes and Mycobacterium tuberculosis. The evidence that such detrimental effects occur during bacterial infections in both animals and humans argues for selective pressure. In this review, we summarize the evidence demonstrating a pro-bacterial role for type I IFNs and discuss possible mechanisms that have been proposed to explain such effects. The theme emerges that type I IFNs act to suppress myeloid cell immune responses. The evolutionary conservation of such anti-inflammatory effects, particularly in the context of infections, suggests they may be important for limiting chronic inflammation. Given the effectiveness of type I IFNs in treatment of certain autoimmune diseases, their production may also act to raise the threshold for activation of immune responses to self-antigens.
    Frontiers in Immunology 09/2014; 5:431. DOI:10.3389/fimmu.2014.00431
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    • "Due to the importance of MAVS in controlling viral infections (Kumar et al., 2006; Sun et al., 2006), one might have expected that the MAVS mRNA would have evolved to contain a highly efficient translational start site. However, our analysis of cis-acting sequences in the MAVS transcript revealed otherwise. "
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    ABSTRACT: Bacterial and viral mRNAs are often polycistronic. Akin to alternative splicing, alternative translation of polycistronic messages is a mechanism to generate protein diversity and regulate gene function. Although a few examples exist, the use of polycistronic messages in mammalian cells is not widely appreciated. Here we report an example of alternative translation as a means of regulating innate immune signaling. MAVS, a regulator of antiviral innate immunity, is expressed from a bicistronic mRNA encoding a second protein, miniMAVS. This truncated variant interferes with interferon production induced by full-length MAVS, whereas both proteins positively regulate cell death. To identify other polycistronic messages, we carried out genome-wide ribosomal profiling and identified a class of antiviral truncated variants. This study therefore reveals the existence of a functionally important bicistronic antiviral mRNA and suggests a widespread role for polycistronic mRNAs in the innate immune system.
    Cell 02/2014; 156(4):800-11. DOI:10.1016/j.cell.2014.01.021 · 32.24 Impact Factor
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