{"gene":"MAVS","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2005,"finding":"MAVS is a mitochondrial outer membrane protein with an N-terminal CARD-like domain and a C-terminal transmembrane domain; both domains are essential for signaling. MAVS activates NF-κB and IRF3 downstream of RIG-I upon viral infection, and its silencing by RNAi abolishes these responses. The transmembrane domain targets MAVS to the mitochondria.","method":"RNAi knockdown, overexpression, epistasis experiments, subcellular fractionation/localization, domain deletion mutagenesis, reporter assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, overexpression, epistasis, domain mutagenesis, localization) in foundational paper, independently replicated by three contemporaneous groups","pmids":["16125763"],"is_preprint":false},{"year":2005,"finding":"MAVS (IPS-1) contains an N-terminal CARD-like domain that mediates direct interaction with the CARD domains of RIG-I and MDA5. TBK1 and IKKi kinases are required downstream of IPS-1 for interferon induction. Knockdown of IPS-1 blocks virus-induced interferon induction.","method":"Functional screening, co-immunoprecipitation (CARD-CARD interaction), siRNA knockdown, kinase requirement assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, siRNA knockdown, kinase dependency assays; replicated across multiple contemporaneous labs","pmids":["16127453"],"is_preprint":false},{"year":2005,"finding":"MAVS (Cardif) interacts with RIG-I via CARD-CARD interaction and recruits IKKα, IKKβ, and IKKε through its C-terminal region to activate NF-κB and IRF3. HCV NS3-4A serine protease cleaves and inactivates Cardif as an immune evasion strategy.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression reporter assays, NS3-4A protease cleavage assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA, protease cleavage assay, replicated independently","pmids":["16177806"],"is_preprint":false},{"year":2005,"finding":"MAVS (VISA) interacts with RIG-I, recruits IRF-3, and acts as a central scaffold. VISA also interacts with TRIF and TRAF6, mediating bifurcation of TLR3-triggered NF-κB and IRF-3 activation pathways. Depletion of VISA inhibits both TLR3-independent and TLR3-dependent IFN-β signaling.","method":"Co-immunoprecipitation, siRNA knockdown, reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs and siRNA knockdown, replicated independently","pmids":["16153868"],"is_preprint":false},{"year":2006,"finding":"HCV NS3-4A protease cleavage of MAVS dissociates it from the mitochondrial outer membrane, disrupting antiviral signaling. IKKε (but not TBK1) co-localizes strongly with MAVS at the mitochondrial membrane, and this co-localization is disrupted by NS3-4A. Mutation of Cys508 to Ala maintains mitochondrial localization in the presence of NS3-4A.","method":"Subcellular fractionation, confocal microscopy, site-directed mutagenesis (C508A), biochemical analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, confocal, mutagenesis) in one study with clear mechanistic resolution","pmids":["16731946"],"is_preprint":false},{"year":2006,"finding":"TRAF3 directly interacts with MAVS (Cardif) via a TRAF-interaction motif (TIM) in MAVS and the TRAF domain of TRAF3. This direct interaction is required for MAVS-mediated type I interferon production; mutations in two critical amino acids in the TRAF domain of TRAF3 that prevent TIM binding abolish IFN production.","method":"Co-immunoprecipitation, site-directed mutagenesis, in vitro binding assays, reporter assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct interaction mapped by mutagenesis, in vitro binding, and functional reporter assays in single lab","pmids":["16858409"],"is_preprint":false},{"year":2006,"finding":"IPS-1 (MAVS) is the sole adapter for both RIG-I and MDA5 signaling in vivo; IPS-1-deficient mice showed severe defects in type I interferon and inflammatory cytokine production and increased susceptibility to RNA (but not DNA) virus infection.","method":"Gene knockout mouse model, viral infection challenge, cytokine/IFN measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with defined phenotypic readout, replicated across multiple virus types","pmids":["16785313"],"is_preprint":false},{"year":2008,"finding":"Crystal structure of the human MAVS CARD domain determined at 2.1 Å resolution. The CARD adopts a six-helix bundle with Greek-key topology and asymmetric surface charge distribution characteristic of homotypic CARD-CARD interactions, with two major polar surfaces on opposite sides of the molecule.","method":"X-ray crystallography (MBP-fusion protein, 2.1 Å resolution)","journal":"BMC structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure, single lab but direct structural determination","pmids":["18307765"],"is_preprint":false},{"year":2008,"finding":"MAVS (Cardif) is cleaved and inactivated by cellular apoptotic caspases activated by various pro-apoptotic signals, resulting in loss of IRF and NF-κB activation capacity. Poliovirus infection triggers caspase-dependent cleavage of Cardif.","method":"Caspase cleavage assay, western blotting, reporter assays, viral infection","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical cleavage assays with viral infection model, single lab","pmids":["18756281"],"is_preprint":false},{"year":2009,"finding":"MAVS induces apoptosis independently of its IFN-I induction function. MAVS-induced apoptosis requires mitochondrial localization and is caspase-dependent. MAVS-/- fibroblasts are resistant to Sendai virus-induced apoptosis. HCV NS3/4A and SARS-CoV NSP15 inhibit MAVS-induced apoptosis.","method":"MAVS knockout fibroblasts, overexpression, caspase inhibitor assay, domain localization, viral protein inhibition screen","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout cells with defined phenotype plus domain requirement analysis, single lab","pmids":["19404494"],"is_preprint":false},{"year":2009,"finding":"PLK1 polo-box domain (PBD) associates with MAVS via two interactions: a phosphodependent interaction at Thr234 within an STP motif in the proline-rich domain, and a phosphoindependent interaction at the C-terminus. PLK1 inhibits MAVS-mediated IRF3/NF-κB activation and IFN induction by disrupting MAVS-TRAF3 association. Depletion of PLK1 increases IFN induction.","method":"Yeast two-hybrid, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus mutagenesis plus functional assays, single lab","pmids":["19546225"],"is_preprint":false},{"year":2011,"finding":"Viral infection induces MAVS to form very large prion-like aggregates on the mitochondrial membrane that potently activate IRF3. Recombinant MAVS CARD-domain fibrils can convert endogenous MAVS into functional aggregates (prion-like behavior). In the presence of K63-linked polyubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates.","method":"Semi-denaturing detergent agarose gel electrophoresis (SDD-AGE), recombinant protein fibril formation, in vitro IRF3 activation assay, cell-free system with purified components","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro prion conversion assay plus SDD-AGE in cells plus cell-free activation, multiple orthogonal methods","pmids":["21782231"],"is_preprint":false},{"year":2011,"finding":"DHX9 helicase interacts with MAVS (IPS-1) via the HelicC-HA2-DUF domain of DHX9 and the CARD domain of IPS-1 to sense dsRNA in myeloid dendritic cells and activate NF-κB and IRF3.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, reporter assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping and functional knockdown, single lab","pmids":["21957149"],"is_preprint":false},{"year":2011,"finding":"IFIT3 bridges MAVS and TBK1 by interacting with TBK1 via its TPR motif (E164/E165) and with the N-terminus of TBK1 (K38), thereby recruiting TBK1 to the MAVS complex on mitochondria and enabling IRF3 phosphorylation.","method":"Co-immunoprecipitation, site-directed mutagenesis, overexpression/knockdown, reporter assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain mutagenesis, functional knockdown, single lab","pmids":["21813773"],"is_preprint":false},{"year":2011,"finding":"PCBP1 mediates constitutive (housekeeping) degradation of MAVS to maintain basal MAVS levels, distinct from the post-infection inhibitor PCBP2. Overexpression of PCBP1 impairs MAVS-mediated antiviral responses; knockdown has the opposite effect.","method":"Overexpression, siRNA knockdown, subcellular fractionation, western blotting, reporter assays","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (knockdown, overexpression, fractionation), single lab","pmids":["22105485"],"is_preprint":false},{"year":2013,"finding":"MAVS directly associates with NLRP3 and facilitates its oligomerization, leading to caspase-1 activation. Mitochondrial localization of MAVS (transmembrane domain) is essential for this function; MAVS-ΔTM does not interact with NLRP3 or trigger its oligomerization.","method":"Co-immunoprecipitation, domain deletion mutagenesis (MAVS-ΔTM), reconstitution in 293T cells, siRNA knockdown in macrophages","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutant and functional reconstitution, single lab","pmids":["24048902"],"is_preprint":false},{"year":2014,"finding":"MAVS specifically activates JNK2 (but not JNK1 or other MAP kinases) through MKK7 to induce apoptosis during viral infection. MAVS recruits MKK7 onto mitochondria via its 3D domain, which phosphorylates JNK2. Jnk2-/- and Mkk7-/- cells cannot initiate virus-induced apoptosis.","method":"Gene knockout cells/mice (Jnk1-/-, Jnk2-/-, Mkk7-/-), domain deletion mutagenesis (3D domain), co-immunoprecipitation, viral challenge","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockout cell lines and mice, domain mapping, Co-IP, clean phenotypic readout","pmids":["24651600"],"is_preprint":false},{"year":2015,"finding":"MAVS harbors two conserved serine/threonine clusters that are phosphorylated by IKK and/or TBK1 in response to viral stimulation. Phosphorylated MAVS binds to a positively charged surface of IRF3, recruiting IRF3 for phosphorylation and activation by TBK1. This phosphorylation-dependent recruitment mechanism is conserved across MAVS, STING, and TRIF.","method":"In vitro kinase assay, site-directed mutagenesis, phosphopeptide binding assay, co-immunoprecipitation, structural analysis of IRF3 surface","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, mutagenesis, phosphopeptide-IRF3 binding with structural rationale, multiple orthogonal methods","pmids":["25636800"],"is_preprint":false},{"year":2016,"finding":"MAVS directly interacts with LC3 through an LC3-binding motif 'YxxI', suggesting MAVS acts as an autophagy receptor for mitochondrial turnover. MAVS self-aggregation and interaction with TRAF2/6 are important for MAVS-mediated mitochondrial autophagy. MAVS activation is sufficient to induce autophagic signaling.","method":"Co-immunoprecipitation, LC3 binding motif mutagenesis, overexpression, autophagy assays","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, motif mutagenesis, functional autophagy readout, single lab","pmids":["27551434"],"is_preprint":false},{"year":2017,"finding":"MAVS activates TBK1/IKKε through TRAFs; TRAFs pre-associated with TBK1/IKKε are recruited to MAVS via direct interaction between TRAF coiled-coil domains and the SDD domain of TBK1/IKKε. TRAF E3 ligase activity synthesizes ubiquitin chains that activate NEMO, which in turn activates IKKα/β to phosphorylate TBK1/IKKε. Cells lacking TRAF2, 3, 5, and 6 completely lose RNA virus responses.","method":"TRAF quadruple knockout cells, NEMO knockout cells, co-immunoprecipitation, reporter assays, epistasis analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — quadruple knockout cells, clean loss-of-function, epistasis across multiple components, single lab with multiple orthogonal approaches","pmids":["29125880"],"is_preprint":false},{"year":2017,"finding":"Subcellular imaging shows that upon RIG-I activation, TRIM25 redistributes to cytoplasmic dots/stress granules while RIG-I associates with both TRIM25/stress granules and mitochondrial MAVS. MAVS competes with TRIM25 for RIG-I binding, suggesting RIG-I moves from TRIM25 to MAVS at mitochondria upon activation. HCV NS3/4A redistributes RIG-I/MAVS and MAVS/MAVS complexes but not RIG-I/TRIM25.","method":"Bimolecular fluorescence complementation (BiFC), super-resolution microscopy, co-immunoprecipitation, viral protein expression","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BiFC and super-resolution imaging plus Co-IP, single lab","pmids":["27807226"],"is_preprint":false},{"year":2019,"finding":"Apoptotic caspase-3 (human cells) and caspase-7 (mouse cells) cleave MAVS (at multiple alternative sites) to prevent cytokine overproduction during viral infection. Caspase-3-deficient cells show elevated type I IFNs without infection, and Casp3-/- mice show increased resistance to viral infection.","method":"Caspase-3/7 knockout cells and mice, in vitro caspase cleavage assay, cytokine measurement, viral challenge","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout cells and mice, in vitro cleavage assay, multiple orthogonal readouts","pmids":["30878284"],"is_preprint":false},{"year":2019,"finding":"TRAF3IP3 accumulates on mitochondria upon virus infection and bridges TRAF3 to MAVS (specifically via MAVS Region III multimerization) to activate TBK1-IRF3. Traf3ip3-deficient mice have severely compromised interferon production and are vulnerable to RNA virus infection.","method":"Co-immunoprecipitation, Traf3ip3 knockout mice, domain analysis (MAVS Region III), viral challenge","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mice with viral phenotype plus Co-IP and domain analysis","pmids":["31390091"],"is_preprint":false},{"year":2019,"finding":"NLK kinase interacts with and phosphorylates MAVS at multiple sites on mitochondria and peroxisomes, inducing MAVS degradation and inactivation of IRF3. NLK depletion promotes antiviral cytokine production; NLK-deficient mice show increased survival after viral infection.","method":"Co-immunoprecipitation, in vitro kinase assay, NLK siRNA/knockout, site-directed mutagenesis, mouse viral challenge","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro kinase assay, knockout/KD cells and mice, multiple orthogonal methods","pmids":["31324787"],"is_preprint":false},{"year":2019,"finding":"Sphingolipid metabolism in astrocytes triggers interaction of the C2 domain of cPLA2 with the CARD domain of MAVS, boosting NF-κB-driven pro-inflammatory transcription in CNS. cPLA2-MAVS interaction also disrupts MAVS-hexokinase 2 (HK2) interaction, decreasing HK2 enzymatic activity and lactate production that supports neurons.","method":"Proteomic, metabolomic, transcriptomic and perturbation studies, co-immunoprecipitation, domain interaction mapping, EAE mouse model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (proteomics, metabolomics, Co-IP, domain mapping, in vivo EAE model)","pmids":["31813625"],"is_preprint":false},{"year":2019,"finding":"RNF115 constitutively interacts with MAVS and induces K48-linked polyubiquitination and proteasomal degradation of MAVS in uninfected cells, keeping basal MAVS levels low. MAVS protein levels are substantially increased in Rnf115-/- cells/organs. After HSV-1 infection, RNF115 switches to catalyzing K63-linked ubiquitination of MITA instead.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, Rnf115-/- mouse cells, western blotting, viral challenge","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse, in vivo ubiquitination assay, multiple orthogonal readouts","pmids":["33139700"],"is_preprint":false},{"year":2020,"finding":"RACK1 interacts with VISA/MAVS and attenuates RIG-I/VISA-mediated antiviral signaling by disrupting formation of VISA-TRAF2, VISA-TRAF3, and VISA-TRAF6 complexes. RACK1 enhances K48-linked ubiquitination of VISA and attenuates its K63-linked ubiquitination.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, in vivo ubiquitination assay, reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional knockdown/overexpression, single lab","pmids":["30527812"],"is_preprint":false},{"year":2021,"finding":"USP18 interacts with MAVS at mitochondria and promotes K63-linked polyubiquitination and subsequent aggregation of MAVS by functioning as a scaffold that facilitates TRIM31 relocalization and enhances TRIM31-MAVS interaction. USP18-deficient mice are more susceptible to RNA virus infection.","method":"Co-immunoprecipitation, in vivo K63-ubiquitination assay, USP18 knockout mice, viral challenge, confocal microscopy","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mice, Co-IP, ubiquitination assay, multiple orthogonal methods","pmids":["34016972"],"is_preprint":false},{"year":2021,"finding":"PRMT7 forms aggregates and catalyzes MAVS arginine monomethylation at R52, attenuating MAVS binding to TRIM31 and RIG-I and suppressing MAVS aggregation. Upon virus infection, PRMT7 undergoes automethylation at R32, SMURF1 is recruited by MAVS to degrade PRMT7, relieving suppression. PRMT7-deficient mice show enhanced antiviral responses.","method":"In vitro methylation assay, co-immunoprecipitation, site-directed mutagenesis (R52, R32), PRMT7 knockout mice, viral challenge","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro methylation assay with mutagenesis, knockout mice, multiple orthogonal methods","pmids":["34171297"],"is_preprint":false},{"year":2021,"finding":"RNF90 promotes K48-linked ubiquitination of MAVS leading to its proteasome-dependent degradation, negatively regulating RNA virus-triggered antiviral innate immune responses. RNF90-deficient cells and mice show enhanced antiviral responses.","method":"RNF90 knockout cells and mice, in vivo ubiquitination assay, co-immunoprecipitation, viral challenge","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout cells and mice, ubiquitination assay, Co-IP, single lab","pmids":["34512666"],"is_preprint":false},{"year":2022,"finding":"PRMT9 directly targets MAVS and catalyzes arginine methylation at Arg41 and Arg43, inhibiting MAVS aggregation and autoactivation in resting cells. Upon virus infection, PRMT9 dissociates from mitochondria, allowing MAVS aggregation and activation.","method":"In vitro methylation assay, site-directed mutagenesis (R41, R43), co-immunoprecipitation, SDD-AGE aggregation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation with site-specific mutagenesis, aggregation assay, single lab with multiple orthogonal methods","pmids":["36028484"],"is_preprint":false},{"year":2022,"finding":"Tankyrases 1/2 (TNKS1/2) translocate from cytosol to mitochondria upon viral infection, interact with MAVS, and catalyze PARylation of MAVS at Glu137, which primes MAVS for K48-linked polyubiquitination by RNF146 and subsequent proteasomal degradation. TNKS1/2-deficient mice produce higher IFN levels and have reduced viral loads.","method":"Co-immunoprecipitation, PARylation assay, site-directed mutagenesis (E137), in vivo ubiquitination assay, TNKS1/2 knockout mice, viral challenge","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical PARylation assay with mutagenesis, knockout mice, multiple orthogonal methods","pmids":["35733260"],"is_preprint":false},{"year":2023,"finding":"MAVS (at peroxisomes) interacts with G6PD and recruits TRAF6 and IRF1 to form the peroxisomal MAVS signalosome, driving glucose flux into the pentose phosphate pathway (PPP) and type III IFN expression. MAMs-located MAVS interacts with glutamine-fructose-6-phosphate transaminase and recruits TRAF6 and TRAF2 to drive glucose flux into HBP and type I IFN expression.","method":"Co-immunoprecipitation, subcellular fractionation, metabolic flux assays, organelle-specific MAVS constructs, reporter assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with organelle-specific constructs and metabolic assays, single lab","pmids":["37660168"],"is_preprint":false},{"year":2023,"finding":"PIAS3-induced poly-SUMOylation of MAVS promotes K63-linked polyubiquitination and aggregation of MAVS. MAVS contains a SUMO-interacting motif (SIM) that enables phase separation and association with IRF3. SENP1 deSUMOylates MAVS to negatively regulate antiviral immunity. IRF3 contains a SIM that mediates its enrichment to MAVS droplets; IRF3 phosphorylation near SIM releases activated IRF3 from MAVS.","method":"Co-immunoprecipitation, site-directed mutagenesis (SIM, SUMOylation sites), phase separation assay, in vitro SUMOylation, SENP1 knockout/overexpression","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro SUMOylation assay, mutagenesis, phase separation assay, multiple orthogonal methods, single lab","pmids":["37188808"],"is_preprint":false},{"year":2023,"finding":"CPT1A recruits ZDHHC4 to catalyze MAVS Cys79-palmitoylation at the ER, promoting MAVS stabilization and activation by inhibiting K48-linked and facilitating K63-linked ubiquitination. Elevated CPT1A increases MAVS palmitoylation and amplifies the IFN-I response.","method":"Co-immunoprecipitation, palmitoylation assay, site-directed mutagenesis (C79), ubiquitination assay, CPT1A modulation, viral and tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical palmitoylation assay with site mutagenesis, ubiquitination assay, multiple cellular and in vivo models","pmids":["38016475"],"is_preprint":false},{"year":2023,"finding":"MAVS is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the transmembrane tail-anchor. Mitochondrial localization of MAVS at resting state depends on the transmembrane domain without Cys508 regulation; however, upon viral infection, Cys508 palmitoylation stabilizes MAVS aggregation on the mitochondrial outer membrane and promotes antiviral signaling.","method":"Site-directed mutagenesis (C508), palmitoylation assay, super-resolution microscopy, biochemical aggregation assays, viral challenge","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific mutagenesis, biochemical palmitoylation assay, super-resolution microscopy, multiple orthogonal methods","pmids":["39141356"],"is_preprint":false},{"year":2023,"finding":"K63-linked polyubiquitin chains loaded onto MAVS (including via unanchored linkage) are recognized by RIG-I CARD to initiate MAVS aggregation, requiring CARD-CARD (RIG-I:MAVS) interaction. Ube2N cooperates with E3 ligases Riplet and TRIM31 to promote unanchored K63-linked polyubiquitination of MAVS; USP10 removes these chains to attenuate RIG-I-mediated MAVS aggregation. USP10-deficient mice show enhanced resistance to RNA virus infection.","method":"In vitro ubiquitination reconstitution, Co-immunoprecipitation, SDD-AGE aggregation assay, USP10 knockout mice, viral challenge","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution, knockout mice, multiple orthogonal methods","pmids":["37582970"],"is_preprint":false},{"year":2023,"finding":"UBL7 promotes K27-linked polyubiquitination of MAVS by interacting with E3 ligase TRIM21 and enhancing TRIM21-MAVS interaction in a dose-dependent manner, facilitating TBK1 recruitment and IFN signaling. UBL7-deficient mice show increased susceptibility to viral infection.","method":"Co-immunoprecipitation, in vivo ubiquitination assay (K27-specific), UBL7 knockout mice, viral challenge","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, knockout mice, single lab","pmids":["36943869"],"is_preprint":false},{"year":2023,"finding":"EBV BILF1 associates with MAVS and the UFM1 E3 ligase UFL1, directing MAVS UFMylation. This triggers MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis, preventing NLRP3 inflammasome activation during EBV replication.","method":"Protein interaction map (AP-MS), co-immunoprecipitation, UFMylation assay, lysosomal degradation assay, BILF1 knockout virus","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS plus Co-IP plus functional validation, single lab","pmids":["37311461"],"is_preprint":false},{"year":2023,"finding":"MAVS directly interacts with MAVS through its interaction with OPA1 (GTPase); MAVS-OPA1 interaction maintains mitochondrial structural integrity in human mesenchymal stem cells. Loss of MAVS or OPA1 leads to mitochondrial dysfunction and accelerated cellular senescence.","method":"CRISPR/Cas9 MAVS knockout, co-immunoprecipitation, mitochondrial structure analysis, MAVS/OPA1 rescue experiments","journal":"Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, CRISPR knockout, rescue experiments, single lab","pmids":["37521327"],"is_preprint":false},{"year":2024,"finding":"MAVS directly interacts with cellular mRNA 3' UTRs through its central intrinsically disordered domain. RNA-dependent organization of the MAVS signalosome is required for IRF3/IRF7 phosphorylation and IFN induction; ribonuclease treatment disrupts the MAVS signalosome and inhibits downstream phosphorylation.","method":"RNA immunoprecipitation, ribonuclease (RNase) treatment, domain deletion mutagenesis (disordered domain), phosphorylation assays, proteomics of signalosome","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct RNA-MAVS binding with domain mapping, RNase disruption of signalosome, multiple orthogonal methods","pmids":["39700280"],"is_preprint":false},{"year":2024,"finding":"ZDHHC24 catalyzes MAVS palmitoylation to promote TBK1-IRF3-IFN signaling; APT2 de-palmitoylates MAVS, inhibiting antiviral signaling. Palmitic acid induces MAVS palmitoylation and aggregation; APT2 inhibitor ML349 reverses MAVS inactivation and enhances antiviral responses.","method":"Palmitoylation assay, ZDHHC24/APT2 overexpression/knockdown, pharmacological inhibition (ML349), MAVS aggregation assay, viral challenge","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical palmitoylation assay with enzyme identification, pharmacological tool compound, multiple orthogonal methods, single lab","pmids":["39255795"],"is_preprint":false},{"year":2020,"finding":"MAVS stabilizes p53 by interacting with it, mediating p53 mitochondrial recruitment under genotoxic stress, and blocking the p53-MDM2 complex formation to inhibit p53 ubiquitination. MAVS knockout mice show decreased resistance to colon cancer in AOM/DSS models.","method":"Co-immunoprecipitation, MAVS knockout mice, tumor challenge (AOM/DSS), ubiquitination assay, p53 localization by fractionation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, knockout mice, ubiquitination assay, single lab","pmids":["31968249"],"is_preprint":false},{"year":2021,"finding":"SARS-CoV-2 Nsp5 promotes SUMOylation of MAVS, increasing MAVS protein stability and leading to NF-κB activation and pro-inflammatory cytokine induction. Knockdown of MAVS or inhibition of SUMOylation attenuates Nsp5-mediated NF-κB activation.","method":"Co-immunoprecipitation, SUMOylation assay, MAVS knockdown, SUMOylation inhibitor treatment, cytokine measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical SUMOylation assay, knockdown rescue, single lab","pmids":["34858407"],"is_preprint":false},{"year":2019,"finding":"MARCH5 E3 ubiquitin ligase targets MAVS protein aggregates for K48-linked ubiquitination and degradation (previously established); additionally targets activated RIG-I oligomers via the RING domain binding to the RIG-I CARD domain, transferring K48-linked polyubiquitin to Lys193 and Lys203 of RIG-I.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, domain mapping (RING domain), site-directed mutagenesis (K193, K203 of RIG-I), proteasome inhibitor assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, in vivo ubiquitination, mutagenesis, single lab","pmids":["31881323"],"is_preprint":false},{"year":2019,"finding":"MAVS CARD domain forms fibrils of smaller than 80 nm in cells (not large prion fibrils as previously modeled). The transmembrane domain of MAVS is required for mitochondrial membrane remodeling, interferon signaling, and pro-apoptotic activities; membrane tethering restrains MAVS polymerization.","method":"Super-resolution light microscopy (STORM/PALM, 32 nm resolution), quantitative image analysis, domain deletion mutagenesis (TM domain), interferon/apoptosis reporter assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — super-resolution microscopy with quantitative analysis plus domain mutagenesis, single lab, challenges prior prion fibril model","pmids":["30715798"],"is_preprint":false},{"year":2008,"finding":"MAVS is expressed from a single gene with 6 exons but generates splice variants (1a, 1b, 1c) with distinct functions. Variant 1b selectively activates IFN-β but not IL-8 promoter and interacts with RIP1 and FADD. The N-terminal CARD domain interacts with RIG-I; putative TRAF2 and TRAF6 binding motifs modulate NF-κB activation.","method":"RT-PCR cloning, overexpression, reporter assays, co-immunoprecipitation","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and functional reporter assays for splice variants, single lab","pmids":["18207245"],"is_preprint":false}],"current_model":"MAVS is a mitochondrial outer membrane adaptor protein that, upon viral infection, is activated downstream of RIG-I and MDA5 through CARD-CARD interactions; activated RIG-I (aided by K63-linked polyubiquitin chains generated by Riplet/TRIM31/Ube2N and removed by USP10) nucleates MAVS into prion-like aggregates, which recruit TRAF2/3/5/6 to activate TBK1/IKKε (bridged by TRAF3IP3, IFIT3, and NAC1) and IKK-NEMO complexes; phosphorylated MAVS then directly recruits IRF3 via a positively charged surface for TBK1-mediated IRF3 activation and IFN-β induction; MAVS activity is tightly regulated by multiple post-translational modifications (K48-ubiquitination by RNF115/RNF90/RNF146/Tankyrases for degradation; K63/K27-ubiquitination for activation; arginine methylation at R41/R43/R52 by PRMT9/PRMT7 to prevent spontaneous aggregation; palmitoylation at Cys508/Cys79 by ZDHHC7/ZDHHC4/ZDHHC24 to stabilize aggregation; SUMOylation; PARylation; phosphorylation by NLK for degradation; phosphorylation by PLK1 to disrupt TRAF3 binding), and is cleaved by viral proteases (HCV NS3-4A at Cys508, HAV 3ABC), cellular caspases, and NLK-driven phosphodegradation; beyond antiviral signaling, MAVS also mediates virus-induced apoptosis (via MKK7-JNK2), NLRP3 inflammasome activation, autophagy (via TRAF6-Beclin-1 and LC3 interaction), metabolic reprogramming (via interactions with G6PD at peroxisomes and GFPT at MAMs), p53 stabilization, and mitochondrial homeostasis (via OPA1 interaction), with subcellular localization at the outer mitochondrial membrane, peroxisomes, and mitochondria-associated ER membranes (MAMs) determining which downstream pathways are preferentially engaged."},"narrative":{"mechanistic_narrative":"MAVS is a mitochondrial outer membrane adaptor protein that serves as the central hub for cytosolic RNA virus sensing, transducing signals from the RIG-I/MDA5 receptors into type I interferon and NF-κB responses [PMID:16125763, PMID:16785313]. Its N-terminal CARD domain engages activated RIG-I and MDA5 through homotypic CARD–CARD interactions, while the C-terminal transmembrane domain anchors it to mitochondria; both are essential for signaling [PMID:16125763, PMID:16127453, PMID:18307765]. Upon activation, RIG-I bound to K63-linked polyubiquitin chains nucleates MAVS into self-propagating prion-like aggregates on the mitochondrial membrane that potently activate IRF3, with membrane tethering restraining polymerization [PMID:21782231, PMID:37582970, PMID:30715798]. Aggregated MAVS recruits TRAF2/3/5/6, which deliver pre-associated TBK1/IKKε and activate NEMO-dependent IKK to phosphorylate the kinases; assembly is bridged by accessory factors including TRAF3IP3 and IFIT3 [PMID:29125880, PMID:31390091, PMID:21813773, PMID:16858409]. Phosphorylated MAVS then directly binds a positively charged surface of IRF3 to license its TBK1-mediated activation and IFN-β induction, a mechanism shared with STING and TRIF [PMID:25636800]. Signalosome organization further depends on direct binding of cellular mRNA 3'UTRs through the MAVS intrinsically disordered region and on SUMO/SIM-driven phase separation [PMID:39700280, PMID:37188808]. MAVS function is governed by an extensive code of post-translational modifications: K63/K27-linked ubiquitination and palmitoylation (ZDHHC4/7/24 at Cys79/Cys508) promote aggregation and activation, whereas K48-linked ubiquitination (RNF115, RNF90, RNF146/Tankyrase-PARylation), arginine methylation (PRMT7/PRMT9 at R41/R43/R52), and phosphodegradation by NLK or PLK1 restrain or terminate signaling [PMID:38016475, PMID:39141356, PMID:39255795, PMID:33139700, PMID:34512666, PMID:35733260, PMID:34171297, PMID:36028484, PMID:31324787, PMID:19546225]. Beyond interferon induction, MAVS independently drives virus-induced apoptosis via an MKK7–JNK2 axis, NLRP3 inflammasome activation, autophagy through LC3 and TRAF6 binding, metabolic reprogramming at peroxisomes and MAMs, and p53 stabilization [PMID:24651600, PMID:24048902, PMID:27551434, PMID:37660168, PMID:31968249]. Its activity is a frequent target of viral immune evasion, exemplified by HCV NS3-4A cleavage at Cys508 that displaces MAVS from mitochondria [PMID:16177806, PMID:16731946].","teleology":[{"year":2005,"claim":"Established the existence and core architecture of a mitochondrial adaptor linking cytosolic RNA receptors to antiviral transcription, answering how RIG-I/MDA5 signals reach IRF3 and NF-κB.","evidence":"RNAi, overexpression, epistasis, domain deletion and subcellular fractionation across four independent groups (MAVS/IPS-1/Cardif/VISA)","pmids":["16125763","16127453","16177806","16153868"],"confidence":"High","gaps":["Mechanism of MAVS activation by upstream receptors not defined","Stoichiometry and higher-order organization unknown"]},{"year":2005,"claim":"Showed MAVS is a target of viral immune evasion, framing it as a physiologically critical node, by demonstrating HCV NS3-4A proteolytic inactivation.","evidence":"NS3-4A protease cleavage assay with reporter readouts","pmids":["16177806"],"confidence":"High","gaps":["Cleavage site and consequence for localization not yet mapped"]},{"year":2006,"claim":"Defined MAVS as the non-redundant adaptor for both RIG-I and MDA5 in vivo and mapped its direct recruitment of TRAF3, establishing genetic necessity and a key effector link.","evidence":"IPS-1 knockout mice with RNA virus challenge; TRAF3-TIM interaction mapping by mutagenesis and in vitro binding; NS3-4A localization studies","pmids":["16785313","16858409","16731946"],"confidence":"High","gaps":["How TRAF recruitment is converted to kinase activation not resolved","DNA virus independence implies pathway boundary not characterized here"]},{"year":2008,"claim":"Determined the MAVS CARD fold and provided structural rationale for homotypic CARD-CARD signaling interactions.","evidence":"X-ray crystallography of the human MAVS CARD at 2.1 Å","pmids":["18307765"],"confidence":"High","gaps":["Structure does not show RIG-I-bound or polymeric state","No information on full-length or membrane-embedded protein"]},{"year":2008,"claim":"Identified caspase cleavage as a regulatory off-switch, addressing how apoptotic signals intersect with antiviral signaling.","evidence":"Caspase cleavage assays and poliovirus infection with reporter readouts","pmids":["18756281"],"confidence":"Medium","gaps":["Cleavage sites and in vivo relevance not defined","Single-lab biochemistry"]},{"year":2011,"claim":"Revealed the central activation mechanism: MAVS forms prion-like aggregates that propagate and amplify signaling, answering how a transient receptor signal is converted to robust IRF3 activation.","evidence":"SDD-AGE, recombinant CARD fibril seeding, and cell-free reconstitution with K63-polyUb and RIG-I","pmids":["21782231"],"confidence":"High","gaps":["Physiological aggregate size and structure debated","How aggregation is spatially limited not addressed here"]},{"year":2011,"claim":"Began assembling the kinase-recruitment scaffold, identifying IFIT3 as a bridge that recruits TBK1 to the MAVS complex.","evidence":"Reciprocal Co-IP, domain mutagenesis, knockdown reporter assays","pmids":["21813773"],"confidence":"Medium","gaps":["Stoichiometry within the signalosome unknown","Single-lab data"]},{"year":2015,"claim":"Solved how MAVS hands the signal to IRF3, showing IKK/TBK1-phosphorylated MAVS directly recruits IRF3 via a charged surface for activation — a mechanism conserved across STING and TRIF.","evidence":"In vitro kinase assays, phosphopeptide-IRF3 binding, mutagenesis with structural rationale","pmids":["25636800"],"confidence":"High","gaps":["Identity of all phosphosites in vivo incompletely defined","Coupling to aggregation state not fully resolved"]},{"year":2017,"claim":"Resolved the kinase-activation logic, showing TRAFs bridge pre-associated TBK1/IKKε to MAVS and TRAF ubiquitin chains activate NEMO/IKK to phosphorylate the kinases.","evidence":"TRAF quadruple-knockout and NEMO-knockout cells with epistasis and Co-IP","pmids":["29125880"],"confidence":"High","gaps":["Precise chain architecture and NEMO sensing details not fully mapped"]},{"year":2019,"claim":"Expanded MAVS beyond interferon to direct effector functions, establishing a dedicated MKK7-JNK2 apoptotic axis and accessory bridging by TRAF3IP3.","evidence":"Jnk1/Jnk2/Mkk7 knockout cells and mice, domain mapping, Co-IP; Traf3ip3 knockout mice with viral challenge","pmids":["24651600","31390091"],"confidence":"High","gaps":["How MAVS selects between IFN, apoptotic, and inflammasome outputs not defined"]},{"year":2019,"claim":"Defined negative regulation of MAVS by kinase-driven degradation and constitutive K48-ubiquitination, explaining how basal levels and signal termination are enforced.","evidence":"NLK kinase assay and knockout mice; RNF115 in vivo ubiquitination and Rnf115-/- cells; caspase-3/7 knockout cells and mice","pmids":["31324787","33139700","30878284"],"confidence":"High","gaps":["Interplay between competing modifications on the same molecule unresolved"]},{"year":2022,"claim":"Established the methylation/PARylation brake that prevents spontaneous MAVS aggregation in resting cells and is relieved upon infection.","evidence":"In vitro methylation and PARylation assays, site mutagenesis (R41/R43/R52, E137), PRMT7/PRMT9/TNKS1/2 knockout mice and SDD-AGE","pmids":["34171297","36028484","35733260"],"confidence":"High","gaps":["How modifications are coordinately reversed upon infection only partly mapped"]},{"year":2023,"claim":"Identified palmitoylation and SUMO-driven phase separation as activating layers that stabilize MAVS aggregation and IRF3 partitioning.","evidence":"Palmitoylation assays with site mutagenesis (Cys79/Cys508) and ZDHHC4/7 identification; SUMOylation, SIM mutagenesis and phase-separation assays","pmids":["38016475","39141356","37188808"],"confidence":"High","gaps":["Temporal ordering of palmitoylation, SUMOylation and ubiquitination unclear"]},{"year":2023,"claim":"Broadened MAVS into a metabolic and homeostatic hub, linking organelle-specific signalosomes to PPP/HBP flux and IFN class, and to mitochondrial integrity via OPA1.","evidence":"Organelle-specific MAVS constructs with metabolic flux assays (G6PD/GFPT at peroxisomes/MAMs); CRISPR MAVS knockout and OPA1 rescue","pmids":["37660168","37521327"],"confidence":"Medium","gaps":["Causal contribution of metabolic outputs to antiviral defense not quantified","Single-lab studies"]},{"year":2024,"claim":"Revealed that signalosome assembly itself requires RNA, with MAVS binding cellular mRNA 3'UTRs through its disordered region to organize IRF3/IRF7 phosphorylation.","evidence":"RNA-IP, RNase disruption, disordered-domain deletion, phosphorylation and proteomic analyses","pmids":["39700280"],"confidence":"High","gaps":["RNA-binding specificity and how RNA integrates with aggregation not fully defined"]},{"year":null,"claim":"How MAVS integrates its many competing modifications, RNA-binding, aggregation state and subcellular location to select among interferon, apoptotic, inflammasome, autophagic and metabolic outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification code to output choice","Quantitative thresholds for aggregation versus degradation unknown","Spatial coordination across mitochondria, peroxisomes and MAMs not mechanistically integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,17,19]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[40]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11,45]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,4,11,27]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[23,32]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[32,34]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,6,17,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4,43]}],"complexes":["MAVS prion-like aggregate/signalosome","NLRP3 inflammasome"],"partners":["RIG-I","TRAF3","TRAF6","TBK1","IRF3","IFIT3","TRAF3IP3","OPA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z434","full_name":"Mitochondrial antiviral-signaling protein","aliases":["CARD adapter inducing interferon beta","Cardif","Interferon beta promoter stimulator protein 1","IPS-1","Putative NF-kappa-B-activating protein 031N","Virus-induced-signaling adapter","VISA"],"length_aa":540,"mass_kda":56.5,"function":"Adapter required for innate immune defense against viruses (PubMed:16125763, PubMed:16127453, PubMed:16153868, PubMed:16177806, PubMed:19631370, PubMed:20127681, PubMed:20451243, PubMed:21170385, PubMed:23087404, PubMed:27992402, PubMed:33139700, PubMed:37582970, PubMed:39589880). Acts downstream of DHX33, RIGI and IFIH1/MDA5, which detect intracellular dsRNA produced during viral replication, to coordinate pathways leading to the activation of NF-kappa-B, IRF3 and IRF7, and to the subsequent induction of antiviral cytokines such as IFNB and RANTES (CCL5) (PubMed:16125763, PubMed:16127453, PubMed:16153868, PubMed:16177806, PubMed:19631370, PubMed:20127681, PubMed:20451243, PubMed:20628368, PubMed:21170385, PubMed:23087404, PubMed:25636800, PubMed:27736772, PubMed:33110251, PubMed:40042308). Peroxisomal and mitochondrial MAVS act sequentially to create an antiviral cellular state (PubMed:20451243). Upon viral infection, peroxisomal MAVS induces the rapid interferon-independent expression of defense factors that provide short-term protection, whereas mitochondrial MAVS activates an interferon-dependent signaling pathway with delayed kinetics, which amplifies and stabilizes the antiviral response (PubMed:20451243). May activate the same pathways following detection of extracellular dsRNA by TLR3 (PubMed:16153868). May protect cells from apoptosis (PubMed:16125763). Involved in NLRP3 inflammasome activation by mediating NLRP3 recruitment to mitochondria (PubMed:23582325)","subcellular_location":"Mitochondrion outer membrane; Mitochondrion; Peroxisome","url":"https://www.uniprot.org/uniprotkb/Q7Z434/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAVS","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAVS","total_profiled":1310},"omim":[{"mim_id":"621401","title":"DEAH-BOX HELICASE 35; DHX35","url":"https://www.omim.org/entry/621401"},{"mim_id":"621348","title":"ZDHHC PALMITOYLTRANSFERASE 12; ZDHHC12","url":"https://www.omim.org/entry/621348"},{"mim_id":"619906","title":"DExD-BOX HELICASE 39A; DDX39A","url":"https://www.omim.org/entry/619906"},{"mim_id":"619535","title":"RING FINGER PROTEIN 115; RNF115","url":"https://www.omim.org/entry/619535"},{"mim_id":"619410","title":"TUBULIN TYROSINE LIGASE-LIKE 12; TTLL12","url":"https://www.omim.org/entry/619410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAVS"},"hgnc":{"alias_symbol":["VISA","KIAA1271","IPS-1","Cardif"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z434","domains":[{"cath_id":"1.10.533.10","chopping":"4-96","consensus_level":"high","plddt":95.7519,"start":4,"end":96}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z434","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z434-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z434-F1-predicted_aligned_error_v6.png","plddt_mean":54.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAVS","jax_strain_url":"https://www.jax.org/strain/search?query=MAVS"},"sequence":{"accession":"Q7Z434","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z434.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z434/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z434"}},"corpus_meta":[{"pmid":"16125763","id":"PMC_16125763","title":"Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16125763","citation_count":2767,"is_preprint":false},{"pmid":"16127453","id":"PMC_16127453","title":"IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.","date":"2005","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16127453","citation_count":2103,"is_preprint":false},{"pmid":"16177806","id":"PMC_16177806","title":"Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16177806","citation_count":1956,"is_preprint":false},{"pmid":"25636800","id":"PMC_25636800","title":"Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.","date":"2015","source":"Science (New York, 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MAVS activates NF-κB and IRF3 downstream of RIG-I upon viral infection, and its silencing by RNAi abolishes these responses. The transmembrane domain targets MAVS to the mitochondria.\",\n      \"method\": \"RNAi knockdown, overexpression, epistasis experiments, subcellular fractionation/localization, domain deletion mutagenesis, reporter assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, overexpression, epistasis, domain mutagenesis, localization) in foundational paper, independently replicated by three contemporaneous groups\",\n      \"pmids\": [\"16125763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAVS (IPS-1) contains an N-terminal CARD-like domain that mediates direct interaction with the CARD domains of RIG-I and MDA5. TBK1 and IKKi kinases are required downstream of IPS-1 for interferon induction. Knockdown of IPS-1 blocks virus-induced interferon induction.\",\n      \"method\": \"Functional screening, co-immunoprecipitation (CARD-CARD interaction), siRNA knockdown, kinase requirement assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, siRNA knockdown, kinase dependency assays; replicated across multiple contemporaneous labs\",\n      \"pmids\": [\"16127453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAVS (Cardif) interacts with RIG-I via CARD-CARD interaction and recruits IKKα, IKKβ, and IKKε through its C-terminal region to activate NF-κB and IRF3. HCV NS3-4A serine protease cleaves and inactivates Cardif as an immune evasion strategy.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression reporter assays, NS3-4A protease cleavage assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA, protease cleavage assay, replicated independently\",\n      \"pmids\": [\"16177806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAVS (VISA) interacts with RIG-I, recruits IRF-3, and acts as a central scaffold. VISA also interacts with TRIF and TRAF6, mediating bifurcation of TLR3-triggered NF-κB and IRF-3 activation pathways. Depletion of VISA inhibits both TLR3-independent and TLR3-dependent IFN-β signaling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs and siRNA knockdown, replicated independently\",\n      \"pmids\": [\"16153868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HCV NS3-4A protease cleavage of MAVS dissociates it from the mitochondrial outer membrane, disrupting antiviral signaling. IKKε (but not TBK1) co-localizes strongly with MAVS at the mitochondrial membrane, and this co-localization is disrupted by NS3-4A. Mutation of Cys508 to Ala maintains mitochondrial localization in the presence of NS3-4A.\",\n      \"method\": \"Subcellular fractionation, confocal microscopy, site-directed mutagenesis (C508A), biochemical analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, confocal, mutagenesis) in one study with clear mechanistic resolution\",\n      \"pmids\": [\"16731946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRAF3 directly interacts with MAVS (Cardif) via a TRAF-interaction motif (TIM) in MAVS and the TRAF domain of TRAF3. This direct interaction is required for MAVS-mediated type I interferon production; mutations in two critical amino acids in the TRAF domain of TRAF3 that prevent TIM binding abolish IFN production.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, in vitro binding assays, reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct interaction mapped by mutagenesis, in vitro binding, and functional reporter assays in single lab\",\n      \"pmids\": [\"16858409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IPS-1 (MAVS) is the sole adapter for both RIG-I and MDA5 signaling in vivo; IPS-1-deficient mice showed severe defects in type I interferon and inflammatory cytokine production and increased susceptibility to RNA (but not DNA) virus infection.\",\n      \"method\": \"Gene knockout mouse model, viral infection challenge, cytokine/IFN measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with defined phenotypic readout, replicated across multiple virus types\",\n      \"pmids\": [\"16785313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of the human MAVS CARD domain determined at 2.1 Å resolution. The CARD adopts a six-helix bundle with Greek-key topology and asymmetric surface charge distribution characteristic of homotypic CARD-CARD interactions, with two major polar surfaces on opposite sides of the molecule.\",\n      \"method\": \"X-ray crystallography (MBP-fusion protein, 2.1 Å resolution)\",\n      \"journal\": \"BMC structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure, single lab but direct structural determination\",\n      \"pmids\": [\"18307765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAVS (Cardif) is cleaved and inactivated by cellular apoptotic caspases activated by various pro-apoptotic signals, resulting in loss of IRF and NF-κB activation capacity. Poliovirus infection triggers caspase-dependent cleavage of Cardif.\",\n      \"method\": \"Caspase cleavage assay, western blotting, reporter assays, viral infection\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical cleavage assays with viral infection model, single lab\",\n      \"pmids\": [\"18756281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAVS induces apoptosis independently of its IFN-I induction function. MAVS-induced apoptosis requires mitochondrial localization and is caspase-dependent. MAVS-/- fibroblasts are resistant to Sendai virus-induced apoptosis. HCV NS3/4A and SARS-CoV NSP15 inhibit MAVS-induced apoptosis.\",\n      \"method\": \"MAVS knockout fibroblasts, overexpression, caspase inhibitor assay, domain localization, viral protein inhibition screen\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout cells with defined phenotype plus domain requirement analysis, single lab\",\n      \"pmids\": [\"19404494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PLK1 polo-box domain (PBD) associates with MAVS via two interactions: a phosphodependent interaction at Thr234 within an STP motif in the proline-rich domain, and a phosphoindependent interaction at the C-terminus. PLK1 inhibits MAVS-mediated IRF3/NF-κB activation and IFN induction by disrupting MAVS-TRAF3 association. Depletion of PLK1 increases IFN induction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus mutagenesis plus functional assays, single lab\",\n      \"pmids\": [\"19546225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Viral infection induces MAVS to form very large prion-like aggregates on the mitochondrial membrane that potently activate IRF3. Recombinant MAVS CARD-domain fibrils can convert endogenous MAVS into functional aggregates (prion-like behavior). In the presence of K63-linked polyubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates.\",\n      \"method\": \"Semi-denaturing detergent agarose gel electrophoresis (SDD-AGE), recombinant protein fibril formation, in vitro IRF3 activation assay, cell-free system with purified components\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro prion conversion assay plus SDD-AGE in cells plus cell-free activation, multiple orthogonal methods\",\n      \"pmids\": [\"21782231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHX9 helicase interacts with MAVS (IPS-1) via the HelicC-HA2-DUF domain of DHX9 and the CARD domain of IPS-1 to sense dsRNA in myeloid dendritic cells and activate NF-κB and IRF3.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping and functional knockdown, single lab\",\n      \"pmids\": [\"21957149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IFIT3 bridges MAVS and TBK1 by interacting with TBK1 via its TPR motif (E164/E165) and with the N-terminus of TBK1 (K38), thereby recruiting TBK1 to the MAVS complex on mitochondria and enabling IRF3 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, overexpression/knockdown, reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain mutagenesis, functional knockdown, single lab\",\n      \"pmids\": [\"21813773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PCBP1 mediates constitutive (housekeeping) degradation of MAVS to maintain basal MAVS levels, distinct from the post-infection inhibitor PCBP2. Overexpression of PCBP1 impairs MAVS-mediated antiviral responses; knockdown has the opposite effect.\",\n      \"method\": \"Overexpression, siRNA knockdown, subcellular fractionation, western blotting, reporter assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (knockdown, overexpression, fractionation), single lab\",\n      \"pmids\": [\"22105485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAVS directly associates with NLRP3 and facilitates its oligomerization, leading to caspase-1 activation. Mitochondrial localization of MAVS (transmembrane domain) is essential for this function; MAVS-ΔTM does not interact with NLRP3 or trigger its oligomerization.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis (MAVS-ΔTM), reconstitution in 293T cells, siRNA knockdown in macrophages\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutant and functional reconstitution, single lab\",\n      \"pmids\": [\"24048902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAVS specifically activates JNK2 (but not JNK1 or other MAP kinases) through MKK7 to induce apoptosis during viral infection. MAVS recruits MKK7 onto mitochondria via its 3D domain, which phosphorylates JNK2. Jnk2-/- and Mkk7-/- cells cannot initiate virus-induced apoptosis.\",\n      \"method\": \"Gene knockout cells/mice (Jnk1-/-, Jnk2-/-, Mkk7-/-), domain deletion mutagenesis (3D domain), co-immunoprecipitation, viral challenge\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockout cell lines and mice, domain mapping, Co-IP, clean phenotypic readout\",\n      \"pmids\": [\"24651600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAVS harbors two conserved serine/threonine clusters that are phosphorylated by IKK and/or TBK1 in response to viral stimulation. Phosphorylated MAVS binds to a positively charged surface of IRF3, recruiting IRF3 for phosphorylation and activation by TBK1. This phosphorylation-dependent recruitment mechanism is conserved across MAVS, STING, and TRIF.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, phosphopeptide binding assay, co-immunoprecipitation, structural analysis of IRF3 surface\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, mutagenesis, phosphopeptide-IRF3 binding with structural rationale, multiple orthogonal methods\",\n      \"pmids\": [\"25636800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAVS directly interacts with LC3 through an LC3-binding motif 'YxxI', suggesting MAVS acts as an autophagy receptor for mitochondrial turnover. MAVS self-aggregation and interaction with TRAF2/6 are important for MAVS-mediated mitochondrial autophagy. MAVS activation is sufficient to induce autophagic signaling.\",\n      \"method\": \"Co-immunoprecipitation, LC3 binding motif mutagenesis, overexpression, autophagy assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, motif mutagenesis, functional autophagy readout, single lab\",\n      \"pmids\": [\"27551434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAVS activates TBK1/IKKε through TRAFs; TRAFs pre-associated with TBK1/IKKε are recruited to MAVS via direct interaction between TRAF coiled-coil domains and the SDD domain of TBK1/IKKε. TRAF E3 ligase activity synthesizes ubiquitin chains that activate NEMO, which in turn activates IKKα/β to phosphorylate TBK1/IKKε. Cells lacking TRAF2, 3, 5, and 6 completely lose RNA virus responses.\",\n      \"method\": \"TRAF quadruple knockout cells, NEMO knockout cells, co-immunoprecipitation, reporter assays, epistasis analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quadruple knockout cells, clean loss-of-function, epistasis across multiple components, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"29125880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Subcellular imaging shows that upon RIG-I activation, TRIM25 redistributes to cytoplasmic dots/stress granules while RIG-I associates with both TRIM25/stress granules and mitochondrial MAVS. MAVS competes with TRIM25 for RIG-I binding, suggesting RIG-I moves from TRIM25 to MAVS at mitochondria upon activation. HCV NS3/4A redistributes RIG-I/MAVS and MAVS/MAVS complexes but not RIG-I/TRIM25.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC), super-resolution microscopy, co-immunoprecipitation, viral protein expression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BiFC and super-resolution imaging plus Co-IP, single lab\",\n      \"pmids\": [\"27807226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Apoptotic caspase-3 (human cells) and caspase-7 (mouse cells) cleave MAVS (at multiple alternative sites) to prevent cytokine overproduction during viral infection. Caspase-3-deficient cells show elevated type I IFNs without infection, and Casp3-/- mice show increased resistance to viral infection.\",\n      \"method\": \"Caspase-3/7 knockout cells and mice, in vitro caspase cleavage assay, cytokine measurement, viral challenge\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout cells and mice, in vitro cleavage assay, multiple orthogonal readouts\",\n      \"pmids\": [\"30878284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF3IP3 accumulates on mitochondria upon virus infection and bridges TRAF3 to MAVS (specifically via MAVS Region III multimerization) to activate TBK1-IRF3. Traf3ip3-deficient mice have severely compromised interferon production and are vulnerable to RNA virus infection.\",\n      \"method\": \"Co-immunoprecipitation, Traf3ip3 knockout mice, domain analysis (MAVS Region III), viral challenge\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mice with viral phenotype plus Co-IP and domain analysis\",\n      \"pmids\": [\"31390091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NLK kinase interacts with and phosphorylates MAVS at multiple sites on mitochondria and peroxisomes, inducing MAVS degradation and inactivation of IRF3. NLK depletion promotes antiviral cytokine production; NLK-deficient mice show increased survival after viral infection.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, NLK siRNA/knockout, site-directed mutagenesis, mouse viral challenge\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro kinase assay, knockout/KD cells and mice, multiple orthogonal methods\",\n      \"pmids\": [\"31324787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sphingolipid metabolism in astrocytes triggers interaction of the C2 domain of cPLA2 with the CARD domain of MAVS, boosting NF-κB-driven pro-inflammatory transcription in CNS. cPLA2-MAVS interaction also disrupts MAVS-hexokinase 2 (HK2) interaction, decreasing HK2 enzymatic activity and lactate production that supports neurons.\",\n      \"method\": \"Proteomic, metabolomic, transcriptomic and perturbation studies, co-immunoprecipitation, domain interaction mapping, EAE mouse model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (proteomics, metabolomics, Co-IP, domain mapping, in vivo EAE model)\",\n      \"pmids\": [\"31813625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RNF115 constitutively interacts with MAVS and induces K48-linked polyubiquitination and proteasomal degradation of MAVS in uninfected cells, keeping basal MAVS levels low. MAVS protein levels are substantially increased in Rnf115-/- cells/organs. After HSV-1 infection, RNF115 switches to catalyzing K63-linked ubiquitination of MITA instead.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, Rnf115-/- mouse cells, western blotting, viral challenge\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse, in vivo ubiquitination assay, multiple orthogonal readouts\",\n      \"pmids\": [\"33139700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RACK1 interacts with VISA/MAVS and attenuates RIG-I/VISA-mediated antiviral signaling by disrupting formation of VISA-TRAF2, VISA-TRAF3, and VISA-TRAF6 complexes. RACK1 enhances K48-linked ubiquitination of VISA and attenuates its K63-linked ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, in vivo ubiquitination assay, reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional knockdown/overexpression, single lab\",\n      \"pmids\": [\"30527812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP18 interacts with MAVS at mitochondria and promotes K63-linked polyubiquitination and subsequent aggregation of MAVS by functioning as a scaffold that facilitates TRIM31 relocalization and enhances TRIM31-MAVS interaction. USP18-deficient mice are more susceptible to RNA virus infection.\",\n      \"method\": \"Co-immunoprecipitation, in vivo K63-ubiquitination assay, USP18 knockout mice, viral challenge, confocal microscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mice, Co-IP, ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"34016972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT7 forms aggregates and catalyzes MAVS arginine monomethylation at R52, attenuating MAVS binding to TRIM31 and RIG-I and suppressing MAVS aggregation. Upon virus infection, PRMT7 undergoes automethylation at R32, SMURF1 is recruited by MAVS to degrade PRMT7, relieving suppression. PRMT7-deficient mice show enhanced antiviral responses.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, site-directed mutagenesis (R52, R32), PRMT7 knockout mice, viral challenge\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro methylation assay with mutagenesis, knockout mice, multiple orthogonal methods\",\n      \"pmids\": [\"34171297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF90 promotes K48-linked ubiquitination of MAVS leading to its proteasome-dependent degradation, negatively regulating RNA virus-triggered antiviral innate immune responses. RNF90-deficient cells and mice show enhanced antiviral responses.\",\n      \"method\": \"RNF90 knockout cells and mice, in vivo ubiquitination assay, co-immunoprecipitation, viral challenge\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout cells and mice, ubiquitination assay, Co-IP, single lab\",\n      \"pmids\": [\"34512666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT9 directly targets MAVS and catalyzes arginine methylation at Arg41 and Arg43, inhibiting MAVS aggregation and autoactivation in resting cells. Upon virus infection, PRMT9 dissociates from mitochondria, allowing MAVS aggregation and activation.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis (R41, R43), co-immunoprecipitation, SDD-AGE aggregation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation with site-specific mutagenesis, aggregation assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36028484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tankyrases 1/2 (TNKS1/2) translocate from cytosol to mitochondria upon viral infection, interact with MAVS, and catalyze PARylation of MAVS at Glu137, which primes MAVS for K48-linked polyubiquitination by RNF146 and subsequent proteasomal degradation. TNKS1/2-deficient mice produce higher IFN levels and have reduced viral loads.\",\n      \"method\": \"Co-immunoprecipitation, PARylation assay, site-directed mutagenesis (E137), in vivo ubiquitination assay, TNKS1/2 knockout mice, viral challenge\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical PARylation assay with mutagenesis, knockout mice, multiple orthogonal methods\",\n      \"pmids\": [\"35733260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAVS (at peroxisomes) interacts with G6PD and recruits TRAF6 and IRF1 to form the peroxisomal MAVS signalosome, driving glucose flux into the pentose phosphate pathway (PPP) and type III IFN expression. MAMs-located MAVS interacts with glutamine-fructose-6-phosphate transaminase and recruits TRAF6 and TRAF2 to drive glucose flux into HBP and type I IFN expression.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, metabolic flux assays, organelle-specific MAVS constructs, reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with organelle-specific constructs and metabolic assays, single lab\",\n      \"pmids\": [\"37660168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIAS3-induced poly-SUMOylation of MAVS promotes K63-linked polyubiquitination and aggregation of MAVS. MAVS contains a SUMO-interacting motif (SIM) that enables phase separation and association with IRF3. SENP1 deSUMOylates MAVS to negatively regulate antiviral immunity. IRF3 contains a SIM that mediates its enrichment to MAVS droplets; IRF3 phosphorylation near SIM releases activated IRF3 from MAVS.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (SIM, SUMOylation sites), phase separation assay, in vitro SUMOylation, SENP1 knockout/overexpression\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro SUMOylation assay, mutagenesis, phase separation assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37188808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A recruits ZDHHC4 to catalyze MAVS Cys79-palmitoylation at the ER, promoting MAVS stabilization and activation by inhibiting K48-linked and facilitating K63-linked ubiquitination. Elevated CPT1A increases MAVS palmitoylation and amplifies the IFN-I response.\",\n      \"method\": \"Co-immunoprecipitation, palmitoylation assay, site-directed mutagenesis (C79), ubiquitination assay, CPT1A modulation, viral and tumor models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical palmitoylation assay with site mutagenesis, ubiquitination assay, multiple cellular and in vivo models\",\n      \"pmids\": [\"38016475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAVS is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the transmembrane tail-anchor. Mitochondrial localization of MAVS at resting state depends on the transmembrane domain without Cys508 regulation; however, upon viral infection, Cys508 palmitoylation stabilizes MAVS aggregation on the mitochondrial outer membrane and promotes antiviral signaling.\",\n      \"method\": \"Site-directed mutagenesis (C508), palmitoylation assay, super-resolution microscopy, biochemical aggregation assays, viral challenge\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific mutagenesis, biochemical palmitoylation assay, super-resolution microscopy, multiple orthogonal methods\",\n      \"pmids\": [\"39141356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"K63-linked polyubiquitin chains loaded onto MAVS (including via unanchored linkage) are recognized by RIG-I CARD to initiate MAVS aggregation, requiring CARD-CARD (RIG-I:MAVS) interaction. Ube2N cooperates with E3 ligases Riplet and TRIM31 to promote unanchored K63-linked polyubiquitination of MAVS; USP10 removes these chains to attenuate RIG-I-mediated MAVS aggregation. USP10-deficient mice show enhanced resistance to RNA virus infection.\",\n      \"method\": \"In vitro ubiquitination reconstitution, Co-immunoprecipitation, SDD-AGE aggregation assay, USP10 knockout mice, viral challenge\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution, knockout mice, multiple orthogonal methods\",\n      \"pmids\": [\"37582970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBL7 promotes K27-linked polyubiquitination of MAVS by interacting with E3 ligase TRIM21 and enhancing TRIM21-MAVS interaction in a dose-dependent manner, facilitating TBK1 recruitment and IFN signaling. UBL7-deficient mice show increased susceptibility to viral infection.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay (K27-specific), UBL7 knockout mice, viral challenge\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, knockout mice, single lab\",\n      \"pmids\": [\"36943869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EBV BILF1 associates with MAVS and the UFM1 E3 ligase UFL1, directing MAVS UFMylation. This triggers MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis, preventing NLRP3 inflammasome activation during EBV replication.\",\n      \"method\": \"Protein interaction map (AP-MS), co-immunoprecipitation, UFMylation assay, lysosomal degradation assay, BILF1 knockout virus\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS plus Co-IP plus functional validation, single lab\",\n      \"pmids\": [\"37311461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAVS directly interacts with MAVS through its interaction with OPA1 (GTPase); MAVS-OPA1 interaction maintains mitochondrial structural integrity in human mesenchymal stem cells. Loss of MAVS or OPA1 leads to mitochondrial dysfunction and accelerated cellular senescence.\",\n      \"method\": \"CRISPR/Cas9 MAVS knockout, co-immunoprecipitation, mitochondrial structure analysis, MAVS/OPA1 rescue experiments\",\n      \"journal\": \"Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, CRISPR knockout, rescue experiments, single lab\",\n      \"pmids\": [\"37521327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAVS directly interacts with cellular mRNA 3' UTRs through its central intrinsically disordered domain. RNA-dependent organization of the MAVS signalosome is required for IRF3/IRF7 phosphorylation and IFN induction; ribonuclease treatment disrupts the MAVS signalosome and inhibits downstream phosphorylation.\",\n      \"method\": \"RNA immunoprecipitation, ribonuclease (RNase) treatment, domain deletion mutagenesis (disordered domain), phosphorylation assays, proteomics of signalosome\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct RNA-MAVS binding with domain mapping, RNase disruption of signalosome, multiple orthogonal methods\",\n      \"pmids\": [\"39700280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC24 catalyzes MAVS palmitoylation to promote TBK1-IRF3-IFN signaling; APT2 de-palmitoylates MAVS, inhibiting antiviral signaling. Palmitic acid induces MAVS palmitoylation and aggregation; APT2 inhibitor ML349 reverses MAVS inactivation and enhances antiviral responses.\",\n      \"method\": \"Palmitoylation assay, ZDHHC24/APT2 overexpression/knockdown, pharmacological inhibition (ML349), MAVS aggregation assay, viral challenge\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical palmitoylation assay with enzyme identification, pharmacological tool compound, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39255795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAVS stabilizes p53 by interacting with it, mediating p53 mitochondrial recruitment under genotoxic stress, and blocking the p53-MDM2 complex formation to inhibit p53 ubiquitination. MAVS knockout mice show decreased resistance to colon cancer in AOM/DSS models.\",\n      \"method\": \"Co-immunoprecipitation, MAVS knockout mice, tumor challenge (AOM/DSS), ubiquitination assay, p53 localization by fractionation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, knockout mice, ubiquitination assay, single lab\",\n      \"pmids\": [\"31968249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARS-CoV-2 Nsp5 promotes SUMOylation of MAVS, increasing MAVS protein stability and leading to NF-κB activation and pro-inflammatory cytokine induction. Knockdown of MAVS or inhibition of SUMOylation attenuates Nsp5-mediated NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assay, MAVS knockdown, SUMOylation inhibitor treatment, cytokine measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical SUMOylation assay, knockdown rescue, single lab\",\n      \"pmids\": [\"34858407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MARCH5 E3 ubiquitin ligase targets MAVS protein aggregates for K48-linked ubiquitination and degradation (previously established); additionally targets activated RIG-I oligomers via the RING domain binding to the RIG-I CARD domain, transferring K48-linked polyubiquitin to Lys193 and Lys203 of RIG-I.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, domain mapping (RING domain), site-directed mutagenesis (K193, K203 of RIG-I), proteasome inhibitor assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, in vivo ubiquitination, mutagenesis, single lab\",\n      \"pmids\": [\"31881323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAVS CARD domain forms fibrils of smaller than 80 nm in cells (not large prion fibrils as previously modeled). The transmembrane domain of MAVS is required for mitochondrial membrane remodeling, interferon signaling, and pro-apoptotic activities; membrane tethering restrains MAVS polymerization.\",\n      \"method\": \"Super-resolution light microscopy (STORM/PALM, 32 nm resolution), quantitative image analysis, domain deletion mutagenesis (TM domain), interferon/apoptosis reporter assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — super-resolution microscopy with quantitative analysis plus domain mutagenesis, single lab, challenges prior prion fibril model\",\n      \"pmids\": [\"30715798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAVS is expressed from a single gene with 6 exons but generates splice variants (1a, 1b, 1c) with distinct functions. Variant 1b selectively activates IFN-β but not IL-8 promoter and interacts with RIP1 and FADD. The N-terminal CARD domain interacts with RIG-I; putative TRAF2 and TRAF6 binding motifs modulate NF-κB activation.\",\n      \"method\": \"RT-PCR cloning, overexpression, reporter assays, co-immunoprecipitation\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and functional reporter assays for splice variants, single lab\",\n      \"pmids\": [\"18207245\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAVS is a mitochondrial outer membrane adaptor protein that, upon viral infection, is activated downstream of RIG-I and MDA5 through CARD-CARD interactions; activated RIG-I (aided by K63-linked polyubiquitin chains generated by Riplet/TRIM31/Ube2N and removed by USP10) nucleates MAVS into prion-like aggregates, which recruit TRAF2/3/5/6 to activate TBK1/IKKε (bridged by TRAF3IP3, IFIT3, and NAC1) and IKK-NEMO complexes; phosphorylated MAVS then directly recruits IRF3 via a positively charged surface for TBK1-mediated IRF3 activation and IFN-β induction; MAVS activity is tightly regulated by multiple post-translational modifications (K48-ubiquitination by RNF115/RNF90/RNF146/Tankyrases for degradation; K63/K27-ubiquitination for activation; arginine methylation at R41/R43/R52 by PRMT9/PRMT7 to prevent spontaneous aggregation; palmitoylation at Cys508/Cys79 by ZDHHC7/ZDHHC4/ZDHHC24 to stabilize aggregation; SUMOylation; PARylation; phosphorylation by NLK for degradation; phosphorylation by PLK1 to disrupt TRAF3 binding), and is cleaved by viral proteases (HCV NS3-4A at Cys508, HAV 3ABC), cellular caspases, and NLK-driven phosphodegradation; beyond antiviral signaling, MAVS also mediates virus-induced apoptosis (via MKK7-JNK2), NLRP3 inflammasome activation, autophagy (via TRAF6-Beclin-1 and LC3 interaction), metabolic reprogramming (via interactions with G6PD at peroxisomes and GFPT at MAMs), p53 stabilization, and mitochondrial homeostasis (via OPA1 interaction), with subcellular localization at the outer mitochondrial membrane, peroxisomes, and mitochondria-associated ER membranes (MAMs) determining which downstream pathways are preferentially engaged.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAVS is a mitochondrial outer membrane adaptor protein that serves as the central hub for cytosolic RNA virus sensing, transducing signals from the RIG-I/MDA5 receptors into type I interferon and NF-\\u03baB responses [#0, #6]. Its N-terminal CARD domain engages activated RIG-I and MDA5 through homotypic CARD\\u2013CARD interactions, while the C-terminal transmembrane domain anchors it to mitochondria; both are essential for signaling [#0, #1, #7]. Upon activation, RIG-I bound to K63-linked polyubiquitin chains nucleates MAVS into self-propagating prion-like aggregates on the mitochondrial membrane that potently activate IRF3, with membrane tethering restraining polymerization [#11, #36, #45]. Aggregated MAVS recruits TRAF2/3/5/6, which deliver pre-associated TBK1/IKK\\u03b5 and activate NEMO-dependent IKK to phosphorylate the kinases; assembly is bridged by accessory factors including TRAF3IP3 and IFIT3 [#19, #22, #13, #5]. Phosphorylated MAVS then directly binds a positively charged surface of IRF3 to license its TBK1-mediated activation and IFN-\\u03b2 induction, a mechanism shared with STING and TRIF [#17]. Signalosome organization further depends on direct binding of cellular mRNA 3'UTRs through the MAVS intrinsically disordered region and on SUMO/SIM-driven phase separation [#40, #33]. MAVS function is governed by an extensive code of post-translational modifications: K63/K27-linked ubiquitination and palmitoylation (ZDHHC4/7/24 at Cys79/Cys508) promote aggregation and activation, whereas K48-linked ubiquitination (RNF115, RNF90, RNF146/Tankyrase-PARylation), arginine methylation (PRMT7/PRMT9 at R41/R43/R52), and phosphodegradation by NLK or PLK1 restrain or terminate signaling [#34, #35, #41, #25, #29, #31, #28, #30, #23, #10]. Beyond interferon induction, MAVS independently drives virus-induced apoptosis via an MKK7\\u2013JNK2 axis, NLRP3 inflammasome activation, autophagy through LC3 and TRAF6 binding, metabolic reprogramming at peroxisomes and MAMs, and p53 stabilization [#16, #15, #18, #32, #42]. Its activity is a frequent target of viral immune evasion, exemplified by HCV NS3-4A cleavage at Cys508 that displaces MAVS from mitochondria [#2, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the existence and core architecture of a mitochondrial adaptor linking cytosolic RNA receptors to antiviral transcription, answering how RIG-I/MDA5 signals reach IRF3 and NF-\\u03baB.\",\n      \"evidence\": \"RNAi, overexpression, epistasis, domain deletion and subcellular fractionation across four independent groups (MAVS/IPS-1/Cardif/VISA)\",\n      \"pmids\": [\"16125763\", \"16127453\", \"16177806\", \"16153868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of MAVS activation by upstream receptors not defined\", \"Stoichiometry and higher-order organization unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed MAVS is a target of viral immune evasion, framing it as a physiologically critical node, by demonstrating HCV NS3-4A proteolytic inactivation.\",\n      \"evidence\": \"NS3-4A protease cleavage assay with reporter readouts\",\n      \"pmids\": [\"16177806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site and consequence for localization not yet mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined MAVS as the non-redundant adaptor for both RIG-I and MDA5 in vivo and mapped its direct recruitment of TRAF3, establishing genetic necessity and a key effector link.\",\n      \"evidence\": \"IPS-1 knockout mice with RNA virus challenge; TRAF3-TIM interaction mapping by mutagenesis and in vitro binding; NS3-4A localization studies\",\n      \"pmids\": [\"16785313\", \"16858409\", \"16731946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRAF recruitment is converted to kinase activation not resolved\", \"DNA virus independence implies pathway boundary not characterized here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Determined the MAVS CARD fold and provided structural rationale for homotypic CARD-CARD signaling interactions.\",\n      \"evidence\": \"X-ray crystallography of the human MAVS CARD at 2.1 \\u00c5\",\n      \"pmids\": [\"18307765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure does not show RIG-I-bound or polymeric state\", \"No information on full-length or membrane-embedded protein\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified caspase cleavage as a regulatory off-switch, addressing how apoptotic signals intersect with antiviral signaling.\",\n      \"evidence\": \"Caspase cleavage assays and poliovirus infection with reporter readouts\",\n      \"pmids\": [\"18756281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage sites and in vivo relevance not defined\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed the central activation mechanism: MAVS forms prion-like aggregates that propagate and amplify signaling, answering how a transient receptor signal is converted to robust IRF3 activation.\",\n      \"evidence\": \"SDD-AGE, recombinant CARD fibril seeding, and cell-free reconstitution with K63-polyUb and RIG-I\",\n      \"pmids\": [\"21782231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological aggregate size and structure debated\", \"How aggregation is spatially limited not addressed here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Began assembling the kinase-recruitment scaffold, identifying IFIT3 as a bridge that recruits TBK1 to the MAVS complex.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mutagenesis, knockdown reporter assays\",\n      \"pmids\": [\"21813773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry within the signalosome unknown\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Solved how MAVS hands the signal to IRF3, showing IKK/TBK1-phosphorylated MAVS directly recruits IRF3 via a charged surface for activation \\u2014 a mechanism conserved across STING and TRIF.\",\n      \"evidence\": \"In vitro kinase assays, phosphopeptide-IRF3 binding, mutagenesis with structural rationale\",\n      \"pmids\": [\"25636800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all phosphosites in vivo incompletely defined\", \"Coupling to aggregation state not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the kinase-activation logic, showing TRAFs bridge pre-associated TBK1/IKK\\u03b5 to MAVS and TRAF ubiquitin chains activate NEMO/IKK to phosphorylate the kinases.\",\n      \"evidence\": \"TRAF quadruple-knockout and NEMO-knockout cells with epistasis and Co-IP\",\n      \"pmids\": [\"29125880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise chain architecture and NEMO sensing details not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded MAVS beyond interferon to direct effector functions, establishing a dedicated MKK7-JNK2 apoptotic axis and accessory bridging by TRAF3IP3.\",\n      \"evidence\": \"Jnk1/Jnk2/Mkk7 knockout cells and mice, domain mapping, Co-IP; Traf3ip3 knockout mice with viral challenge\",\n      \"pmids\": [\"24651600\", \"31390091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MAVS selects between IFN, apoptotic, and inflammasome outputs not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined negative regulation of MAVS by kinase-driven degradation and constitutive K48-ubiquitination, explaining how basal levels and signal termination are enforced.\",\n      \"evidence\": \"NLK kinase assay and knockout mice; RNF115 in vivo ubiquitination and Rnf115-/- cells; caspase-3/7 knockout cells and mice\",\n      \"pmids\": [\"31324787\", \"33139700\", \"30878284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between competing modifications on the same molecule unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the methylation/PARylation brake that prevents spontaneous MAVS aggregation in resting cells and is relieved upon infection.\",\n      \"evidence\": \"In vitro methylation and PARylation assays, site mutagenesis (R41/R43/R52, E137), PRMT7/PRMT9/TNKS1/2 knockout mice and SDD-AGE\",\n      \"pmids\": [\"34171297\", \"36028484\", \"35733260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How modifications are coordinately reversed upon infection only partly mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified palmitoylation and SUMO-driven phase separation as activating layers that stabilize MAVS aggregation and IRF3 partitioning.\",\n      \"evidence\": \"Palmitoylation assays with site mutagenesis (Cys79/Cys508) and ZDHHC4/7 identification; SUMOylation, SIM mutagenesis and phase-separation assays\",\n      \"pmids\": [\"38016475\", \"39141356\", \"37188808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal ordering of palmitoylation, SUMOylation and ubiquitination unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened MAVS into a metabolic and homeostatic hub, linking organelle-specific signalosomes to PPP/HBP flux and IFN class, and to mitochondrial integrity via OPA1.\",\n      \"evidence\": \"Organelle-specific MAVS constructs with metabolic flux assays (G6PD/GFPT at peroxisomes/MAMs); CRISPR MAVS knockout and OPA1 rescue\",\n      \"pmids\": [\"37660168\", \"37521327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of metabolic outputs to antiviral defense not quantified\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed that signalosome assembly itself requires RNA, with MAVS binding cellular mRNA 3'UTRs through its disordered region to organize IRF3/IRF7 phosphorylation.\",\n      \"evidence\": \"RNA-IP, RNase disruption, disordered-domain deletion, phosphorylation and proteomic analyses\",\n      \"pmids\": [\"39700280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding specificity and how RNA integrates with aggregation not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAVS integrates its many competing modifications, RNA-binding, aggregation state and subcellular location to select among interferon, apoptotic, inflammasome, autophagic and metabolic outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification code to output choice\", \"Quantitative thresholds for aggregation versus degradation unknown\", \"Spatial coordination across mitochondria, peroxisomes and MAMs not mechanistically integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 17, 19]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [40]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11, 45]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 4, 11, 27]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [23, 32]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [32, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 6, 17, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4, 43]}\n    ],\n    \"complexes\": [\"MAVS prion-like aggregate/signalosome\", \"NLRP3 inflammasome\"],\n    \"partners\": [\"RIG-I\", \"TRAF3\", \"TRAF6\", \"TBK1\", \"IRF3\", \"IFIT3\", \"TRAF3IP3\", \"OPA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}