Alternative titles; symbols
HGNC Approved Gene Symbol: MAVS
Cytogenetic location: 20p13 Genomic coordinates (GRCh38) : 20:3,846,834-3,876,118 (from NCBI)
Double-stranded RNA viruses are recognized in a cell type-dependent manner by the transmembrane receptor TLR3 (603029) or by the cytoplasmic RNA helicases MDA5 (606951) and RIGI (DDX58; 609631). These interactions initiate signaling pathways that differ in their initial steps but converge in the activation of the protein kinases IKKA (CHUK; 600664) and IKKB (IKBKB; 603258), which activate NFKB (see 164011), or TBK1 (604834) and IKKE (IKBKE; 605048), which activate IRF3 (603734). Activated IRF3 and NFKB induce transcription of IFNB (IFNB1; 147640). For the TLR3 pathway, the intermediary molecule before the pathways converge is the cytoplasmic protein TRIF (TICAM1; 607601). For RIGI, the intermediary protein is mitochondria-bound IPS1 (Sen and Sarkar, 2005).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (1999) cloned KIAA1271. The transcript contains several repetitive elements in its 3-prime UTR, and the deduced protein contains 542 amino acids. RT-PCR ELISA detected intermediate expression in all tissues and specific brain regions examined except testis and fetal brain, in which expression was low.
By screening for proteins that activated the NFKB and MAPK (see MAPK1; 176948) signaling pathways, followed by database analysis, Xu et al. (2005) identified 2 VISA splice variants. Both transcripts encode a deduced 540-amino acid protein with an N-terminal CARD module followed by a TRAF2 (601895)-binding motif and 2 TRAF6 (602355)-binding motifs. Northern blot analysis detected 9.5- and 3.4-kb VISA transcripts in all tissues examined. Western blot analysis detected endogenous VISA at about 62 kD in human cell lines.
Independently, Seth et al. (2005), Kawai et al. (2005), and Meylan et al. (2005) also cloned and characterized VISA, which they called MAVS, IPS1, and CARDIF, respectively. Seth et al. (2005) identified a C-terminal transmembrane domain in MAVS that targets the protein to mitochondria.
Xu et al. (2005) demonstrated that VISA is critical in the IFNB (147640) signaling pathway and is required for both Sendai virus-triggered TLR3-mediated and TLR3-independent signaling. In the TLR3-mediated signaling pathway, VISA interacted with TRIF and TRAF6 and mediated bifurcation of the NFKB and IFN-stimulated response element (ISRE) activation pathways. In the TLR3-independent signaling pathway, VISA and RIGI interacted via their respective CARD modules, and VISA functioned as an adaptor to recruit downstream components, such as IRF3, to the RIGI complex. Xu et al. (2005) concluded that VISA plays essential roles in antiviral responses by participating in 2 virus-triggered IFN signaling pathways.
Seth et al. (2005) showed that silencing of MAVS through RNA interference abolished NFKB and IRF3 activation by viruses, leading to increased viral replication. In contrast, MAVS overexpression induced IFNB expression following NFKB and IRF3 activation. Additional interference, knockdown, and mutation analyses indicated that MAVS functions downstream of RIGI and that its CARD is essential for MAVS signaling. Seth et al. (2005) confirmed by mutation analysis, confocal microscopy, and subcellular fractionation that the C-terminal transmembrane domain of MAVS is required for IFNB activation and for localization to the outer mitochondrial membrane. When targeted to other membrane locations, MAVS failed to activate IFNB. Seth et al. (2005) concluded that MAVS function leads to stronger antiviral immunity and proposed that mitochondria may have a role in innate immunity.
Kawai et al. (2005) also characterized IPS1 function and found that the CARD of IPS1 interacted with the CARDs of RIGI and MDA5. Overexpression of IPS1 resulted in activation of IFNB, IP10 (CXCL10; 147310), and RANTES (CCL5; 187011). IPS1 overexpression also enhanced IFNA4 (147564) and IFNA6 (147566) expression when coexpressed with IRF7 (605047).
In addition to the interactions documented by Seth et al. (2005) and Kawai et al. (2005), Meylan et al. (2005) found that the NS3-4A serine protease from hepatitis C virus (HCV; see 609532) targets and inactivates CARDIF. They determined that NS3-4A cleaves CARDIF after cys508, thereby blocking IRF3 activation and IFNB production.
Independently, Li et al. (2005) demonstrated that HCV NS3-4A cleaves MAVS at cys508. Immunoprecipitation analysis and confocal microscopy showed that NS3-4A bound to and colocalized with MAVS in mitochondria. Li et al. (2005) proposed that sequence variation in MAVS might account for the exposed individuals who mount a successful immune response against HCV and other viruses that inhibit IFN production by attacking MAVS or other mitochondrial proteins.
Moore et al. (2008) showed that NLRX1 (611947), a highly conserved nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing (NLR) family member, localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 resulted in the potent inhibition of RIG (609631)-like helicase (RLH) family and MAVS-mediated IFNB promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promoted virus-induced type I interferon (see 147570) production and decreased viral replication. Moore et al. (2008) concluded that their work identified NLRX1 as a check against mitochondrial antiviral responses and represented an intersection of 3 ancient cellular processes: NLR signaling, intracellular virus detection, and the use of mitochondria as a platform for antipathogen signaling. They also concluded that their work represented a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identified a key therapeutic target for enhancing antiviral responses.
Using a cell-free system, Hou et al. (2011) showed that after viral infection MAVS formed large aggregates that potently activated IRF3. The aggregates formed self-perpetuating, fiber-like polymers that efficiently converted endogenous MAVS into functional aggregates. These properties closely resembled those of prions (see 176640), including fibrous aggregates, detergent and protease resistance, and the ability to 'infect' endogenous protein and convert the native conformation into fibrous aggregates. The formation of MAVS aggregates resulted in a gain of function, and the conformational change was tightly regulated by viral infection. Incubation of endogenous MAVS with RIGI, mitochondria, and lys63-linked polyubiquitin chains also converted MAVS into functional aggregates. Hou et al. (2011) proposed that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.
Using a small interfering RNA screen, Wang et al. (2013) found that human UBXN1 (616378) exhibited the strongest inhibitory effect on RNA-virus-induced interferon promoter activity compared with other UBXN family members. They demonstrated that, after viral infection, UBXN1 bound MAVS and disrupted the MAVS-TRAF3 (601896)/TRAF6 signaling complex, as well as downstream antiviral immune responses.
Cai et al. (2014) found that the N-terminal CARD of MAVS and the N-terminal PYRIN domain of ASC (PYCARD; 606838) functioned as prions in yeast and that their prion forms were inducible by their respective upstream activators. Similarly, a yeast prion domain could functionally replace the CARD and PYRIN domains in mammalian cell signaling. Mutations in MAVS or ASC that disrupted their prion activities in yeast also abrogated their ability to signal in mammalian cells. The recombinant PYRIN domain of ASC formed prion-like fibers that could convert inactive ASC into functional polymers capable of activating CASP1 (147678). A conserved fungal NOD-like receptor and prion pair could functionally reconstitute signaling of the NLRP3 (606416) and ASC PYRIN domains in mammalian cells. Cai et al. (2014) proposed that prion-like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation.
Brubaker et al. (2014) noted that Seth et al. (2005) had reported the detection of 72- and 50-kD MAVS proteins. Brubaker et al. (2014) found that none of the MAVS splice variants corresponded to the 50-kD product, which they termed miniMAVS. In vitro transcription and translation showed that both miniMAVS and the full-length, 72-kD MAVS protein were expressed from the MAVS coding region. Mutation of met1 or met142 of MAVS eliminated generation of full-length MAVS and miniMAVS, respectively. Comparative sequence analysis indicated that met142 is conserved in primates, but not rodents. Brubaker et al. (2014) concluded that MAVS is bicistronic and that miniMAVS is the product of a unique ORF downstream of the start site for full-length MAVS. Moreover, they identified cis regulatory elements in the 5-prime UTR of MAVS that explained the translation efficiency of full-length MAVS and miniMAVS. Brubaker et al. (2014) found that miniMAVS interfered with the signaling function of full-length MAVS. Both full-length MAVS and miniMAVS positively regulated cell death. Ribosomal profiling predicted that additional bicistronic mRNAs may also encode truncated protein variants involved in the regulation of innate immunity.
Using biochemical and mouse cell- and human cell-based assays, Liu et al. (2015) found that both MAVS and STING (612374) interacted with IRF3 (603734) in a phosphorylation-dependent manner. The authors showed that both MAVS and STING are phosphorylated in response to stimulation at their respective C-terminal pLxIS consensus motifs (p, hydrophilic residue; x, any residue; S, phosphorylation site). This phosphorylation event then recruits IRF3 to the active adaptor protein and is essential for IRF3 activation. Point mutations that impair the phosphorylation of MAVS or STING at their consensus motif abrogated IRF3 binding and subsequent interferon (see 147660) induction. Liu et al. (2015) found that MAVS is phosphorylated by the kinases TBK1 (604834) and IKK (see 600664), whereas STING is phosphorylated by TBK1. Phosphorylated MAVS and STING subsequently bind to conserved, positively charged surfaces of IRF3, thereby recruiting IRF3 for its phosphorylation and activation by TBK1. Liu et al. (2015) also showed that TRIF (607601)-mediated activation of IRF3 depends of TRIF phosphorylation at the pLxIS motif commonly found in MAVS, STING, and IRF3. The authors concluded that phosphorylation of innate immune adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate type I interferon production.
Okamoto et al. (2014) noted that the TLR3-TICAM1 pathway is essential for production of type III interferon (e.g., IFNL1; 607403) in response to HCV infection. Using Ips1-knockout mice, they showed that Ips1 was essential for production of type III interferons by mouse hepatocytes and Cd8-positive dendritic cells in response to cytoplasmic HCV RNA. In turn, type III interferons induced expression of Rigi, but not Tlr3, in dendritic cells and augmented production of type III interferon, but not activation of natural killer cells. In addition, both Ifna and Ifnl3 (607402) induced the cytoplasmic antiviral proteins Isg20 (604533), Mx1 (147150), and RNase L (RNASEL; 180435). Okamoto et al. (2014) concluded that multiple mechanisms, including an IPS1-dependent pathway, are involved in type III interferon production in response to HCV RNA, and that these lead to the expression of cytoplasmic antiviral proteins.
Hirai-Yuki et al. (2016) described a murine model of hepatitis A virus (HAV) infection that recapitulated critical features of type A hepatitis in humans, and demonstrated that the capacity of HAV to evade MAVS-mediated type I interferon responses defines its host species range. HAV-induced liver injury was associated with interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation that unexpectedly resulted from MAVS and IRF3/IRF7 signaling. This murine model thus revealed a link between innate immune responses to virus infection and acute liver injury, providing a paradigm for viral pathogenesis in the liver.
Using luciferase analysis, Nie et al. (2017) found that overexpression of GPATCH3 (617486) reduced viral activation of the IFNB promoter in a dose-dependent manner in transfected human cells. Knockdown of GPATCH3 enhanced viral activation of the IFNB promoter and viral-induced phosphorylation of TBK1 and IRF3, hallmarks of activation of RLR-mediated signaling. Coimmunoprecipitation analysis showed that endogenous GPATCH3 weakly interacted with VISA in uninfected 293T cells and that the interaction increased in virus-infected cells. Domain analysis showed that GPATCH3 interacted with the C-terminal transmembrane domain of VISA. GPATCH3 interacted with VISA in mitochondria, but not in peroxisomes. GPATCH3 mediated disruption of VISA-associated complexes, leading to negative regulation of RLR-mediated signaling.
Using mass spectrometric analysis, Aoyama-Ishiwatari et al. (2021) showed that NUDT21 (604978) formed a complex with mitochondrial IPS1 in HEK293T cells. The interaction required the N-terminal domains of IPS1, including the CARD and the proline-rich domain. A fraction of NUDT21 and IPS1 localized to mitochondria, but in the presence of cytoplasmic double-stranded RNA (dsRNA), they became localized to cytoplasmic stress granules (SGs) containing RLRs. NUDT21 mediated antiviral cellular responses induced by cytoplasmic dsRNA and was implicated in optimal induction of IFN-beta in response to viral infection. Similarly, forced localization of IPS1 to SGs promoted IFN-beta induction in response to cytoplasmic dsRNA, suggesting that NUDT21-mediated localization of IPS1 to SGs enhanced IFN induction in the presence of cytoplasmic dsRNA.
By radiation hybrid analysis, Nagase et al. (1999) mapped the KIAA1271 gene to chromosome 20.
Gross (2015) mapped the MAVS gene to chromosome 20p13 based on an alignment of the MAVS sequence (GenBank AB232371) with the genomic sequence (GRCh38).
Sun et al. (2006) found that deletion of Mavs in mice abolished viral induction of interferon and prevented activation of Nfkb and Irf3 in multiple cell types, but not plasmacytoid dendritic cells. Interferon expression in response to cytosolic DNA or Listeria monocytogenes was not affected by Mavs deficiency, and viability and fertility were not compromised. Mavs -/- mice challenged with vesicular stomatitis virus had significantly higher viral titers than Mavs +/- or wildtype mice 12 to 48 hours after infection, but not 72 hours after infection. Mavs -/- and Mavs +/- mice, but not most wildtype mice, succumbed to infection in a dose- and Mavs-dependent manner. Sun et al. (2006) concluded that cytosolic viral signaling through MAVS is required for innate immune responses against viral infection.
Kumar et al. (2006) found that Ips1-deficient mice had defective induction of type I Ifn and inflammatory cytokines after infection with various RNA viruses and were susceptible to the RNA virus infection. However, Ips1 was not essential for responses to DNA viruses. Kumar et al. (2006) concluded that IPS1 is an essential component in RIGI- and MDA5-dependent signaling that triggers the host response to infection with various RNA viruses.
The article by Zeng et al. (2014) reporting that deficiency of MAVS and/or cGAS causes a robust decrease in type II T-independent B-cell responses was retracted by the editors of Science (Berg, 2017) because the majority of the authors agreed that the core observations and conclusions of the article could not be replicated and requested a retraction.
Aoyama-Ishiwatari, S., Okazaki, T., Iemura, S., Natsume, T., Okada, Y., Gotoh, Y. NUDT21 links mitochondrial IPS-1 to RLR-containing stress granules and activates host antiviral defense. J. Immun. 206: 154-163, 2021. [PubMed: 33219146] [Full Text: https://doi.org/10.4049/jimmunol.2000306]
Berg, J. Editorial Retraction. Science 358: 458 only, 2017. [PubMed: 29074761] [Full Text: https://doi.org/10.1126/science.aar2406]
Brubaker, S. W., Gauthier, A. E., Mills, E. W., Ingolia, N. T., Kagan, J. C. A bicistronic MAVS transcript highlights a class of truncated variants in antiviral immunity. Cell 156: 800-811, 2014. [PubMed: 24529381] [Full Text: https://doi.org/10.1016/j.cell.2014.01.021]
Cai, X., Chen, J., Xu, H., Liu, S., Jiang, Q.-X., Halfmann, R., Chen, Z. J. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156: 1207-1222, 2014. [PubMed: 24630723] [Full Text: https://doi.org/10.1016/j.cell.2014.01.063]
Gross, M. B. Personal Communication. Baltimore, Md. 9/2/2015.
Hirai-Yuki, A., Hensley, L., McGivern, D. R., Gonzalez-Lopez, O., Das, A., Feng, H., Sun, L., Wilson, J. E., Hu, F., Feng, Z., Lovell, W., Misumi, I., Ting, J. P.-Y., Montgomery, S., Cullen, J., Whitmire, J. K., Lemon, S. M. MAVS-dependent host species range and pathogenicity of human hepatitis A virus. Science 353: 1541-1545, 2016. [PubMed: 27633528] [Full Text: https://doi.org/10.1126/science.aaf8325]
Hou, F., Sun, L., Zheng, H., Skaug, B., Jiang, Q.-X., Chen, Z. J. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146: 448-461, 2011. Note: Erratum: Cell 146: 841 only, 2011. [PubMed: 21782231] [Full Text: https://doi.org/10.1016/j.cell.2011.06.041]
Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K. J., Takeuchi, O., Akira, S. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nature Immun. 6: 981-988, 2005. [PubMed: 16127453] [Full Text: https://doi.org/10.1038/ni1243]
Kumar, H., Kawai, T., Kato, H., Sato, S., Takahashi, K., Coban, C., Yamamoto, M., Uematsu, S., Ishii, K. J., Takeuchi, O., Akira, S. Essential role of IPS-1 in innate immune responses against RNA viruses. J. Exp. Med. 203: 1795-1803, 2006. [PubMed: 16785313] [Full Text: https://doi.org/10.1084/jem.20060792]
Li, X.-D., Sun, L., Seth, R. B., Pineda, G., Chen, Z. J. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Nat. Acad. Sci. 102: 17717-17722, 2005. [PubMed: 16301520] [Full Text: https://doi.org/10.1073/pnas.0508531102]
Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y.-T., Grishin, N. V., Chen, Z. J. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347: aaa2630, 2015. Mote: Electronic Article. [PubMed: 25636800] [Full Text: https://doi.org/10.1126/science.aaa2630]
Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., Tschopp, J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437: 1167-1172, 2005. [PubMed: 16177806] [Full Text: https://doi.org/10.1038/nature04193]
Moore, C. B., Bergstralh, D. T., Duncan, J. A., Lei, Y., Morrison, T. E., Zimmerman, A. G., Accavitti-Loper, M. A., Madden, V. J., Sun, L., Ye, Z., Lich, J. D., Heise, M. T., Chen, Z., Ting, J. P.-Y. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451: 573-577, 2008. [PubMed: 18200010] [Full Text: https://doi.org/10.1038/nature06501]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Nie, Y., Ran, Y., Zhang, H.-Y., Huang, Z.-F., Pan, Z.-Y., Wang, S.-Y., Wang, Y.-Y. GPATCH3 negatively regulates RLR-mediated innate antiviral responses by disrupting the assembly of VISA signalosome. PLoS Pathog. 13: e1006328, 2017. [PubMed: 28414768] [Full Text: https://doi.org/10.1371/journal.ppat.1006328]
Okamoto, M., Oshiumi, H., Azuma, M., Kato, N., Matsumoto, M., Seya, T. IPS-1 is essential for type III IFN production by hepatocytes and dendritic cells in response to hepatitis C virus infection. J. Immun. 192: 2770-2777, 2014. [PubMed: 24532585] [Full Text: https://doi.org/10.4049/jimmunol.1301459]
Sen, G. C., Sarkar, S. N. Hitching RIG to action. Nature Immun. 6: 1074-1076, 2005. [PubMed: 16239922] [Full Text: https://doi.org/10.1038/ni1105-1074]
Seth, R. B., Sun, L., Ea, C.-K., Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappa-B and IRF3. Cell 122: 669-682, 2005. [PubMed: 16125763] [Full Text: https://doi.org/10.1016/j.cell.2005.08.012]
Sun, Q., Sun, L., Liu, H.-H., Chen, X., Seth, R. B., Forman, J., Chen, Z. J. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24: 633-642, 2006. [PubMed: 16713980] [Full Text: https://doi.org/10.1016/j.immuni.2006.04.004]
Wang, P., Yang, L., Cheng, G., Yang, G., Xu, Z., You, F., Sun, Q., Lin, R., Fikrig, E., Sutton, R. E. UBXN1 interferes with Rig-I-like receptor-mediated antiviral immune response by targeting MAVS. Cell Rep. 3: 1057-1070, 2013. [PubMed: 23545497] [Full Text: https://doi.org/10.1016/j.celrep.2013.02.027]
Xu, L.-G., Wang, Y.-Y., Han, K.-J., Li, L.-Y., Zhai, Z., Shu, H.-B. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Molec. Cell 19: 727-740, 2005. [PubMed: 16153868] [Full Text: https://doi.org/10.1016/j.molcel.2005.08.014]
Zeng, M., Hu, Z., Shi, X., Li, X., Zhan, X., Li, X.-D., Wang, J., Choi, J. H., Wang, K., Purrington, T., Tang, M., Fina, M., DeBerardinis, R. J., Moresco, E. M. Y., Pedersen, G., McInerney, G. M., Karlsson Hedestam, G. B., Chen, Z. J., Beutler, B. MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346: 1486-1492, 2014. Note: Retraction: Science 358: 458 only, 2017. [PubMed: 25525240] [Full Text: https://doi.org/10.1126/science.346.6216.1486]