{"gene":"RIGI","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2006,"finding":"RIG-I (DDX58) is essential for type I interferon production in response to paramyxoviruses, influenza virus, and Japanese encephalitis virus in fibroblasts and conventional dendritic cells, while MDA5 is critical for picornavirus detection; RIG-I and MDA5 recognize distinct RNA virus classes in vivo.","method":"Gene-targeted RIG-I knockout and MDA5 knockout mice; interferon induction assays; viral challenge experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype, replicated across multiple virus families and two independent KO models","pmids":["16625202"],"is_preprint":false},{"year":2006,"finding":"5'-triphosphate RNA (3pRNA) is the molecular ligand for RIG-I; the 5'-triphosphate end generated by viral polymerases directly binds RIG-I and activates interferon responses, whereas capping or nucleoside modification of the 5'-triphosphate abrogates detection.","method":"Direct binding assay (5'-triphosphate RNA to RIG-I); phosphatase sensitivity assay; genomic RNA from negative-strand RNA viruses; interferon-alpha response assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding demonstrated, phosphatase sensitivity controls, replicated across multiple labs subsequently","pmids":["17038590"],"is_preprint":false},{"year":2005,"finding":"RIG-I is required for induction of type I interferons via IRF3 activation through IκB kinase-related kinases in fibroblasts and conventional dendritic cells after RNA virus infection; plasmacytoid DCs use the TLR system rather than RIG-I for viral detection.","method":"Gene-targeted RIG-I knockout mice; IFN induction assays; cell-type-specific analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cell-type-specific phenotype, pathway placement via IRF3 and IKK-related kinases","pmids":["16039576"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of RIG-I in complex with dsRNA reveals that dsRNA is sheathed within a network including helicase domains HEL1 and HEL2, an insertion domain HEL2i, and a C-terminal regulatory domain (CTD); a V-shaped pincer connects HEL2 and CTD, coupling RNA binding with ATP hydrolysis.","method":"X-ray crystallography of RIG-I:dsRNA complex","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional domain architecture fully resolved","pmids":["22000018"],"is_preprint":false},{"year":2010,"finding":"Physiological RIG-I agonists during influenza A virus or Sendai virus infection are exclusively generated by virus replication and correspond to full-length virus genomes bearing 5'-triphosphates; non-genomic viral transcripts, short replication intermediates, and cleaved self-RNA do not substantially contribute to interferon induction.","method":"Three orthogonal approaches (RNA immunoprecipitation, biochemical fractionation, genetic approaches) to identify RIG-I agonists in infected cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, two virus systems, rigorous controls","pmids":["20144762"],"is_preprint":false},{"year":2015,"finding":"DDX58 (RIG-I) mutations in ATP-binding motifs (C268F and E373A) confer constitutive RIG-I activation and cause atypical Singleton-Merten syndrome with increased interferon activity and IFN-stimulated gene expression; C268 and E373 residues are located close to ADP and RNA binding sites.","method":"Exome sequencing; functional assays measuring IFN activity and ISG expression; structural analysis of mutant positions; cytopathic assays in human trabecular meshwork cells","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-of-function mutagenesis with IFN activity assays, structural context, disease-linked mutations in two independent families","pmids":["25620203"],"is_preprint":false},{"year":2015,"finding":"RIG-I CARDs must form homo-tetramers (lock-washer configuration) to interact with MAVS and nucleate MAVS filament formation, which is a prerequisite for downstream signaling; TRIM25-mediated K63-linked polyubiquitination stabilizes the 2CARD tetramer.","method":"Structural analysis; biochemical reconstitution of CARD oligomerization; MAVS filament formation assays","journal":"Current Opinion in Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review summarizing reconstitution and structural data from primary papers; mechanistic model supported by biochemical evidence","pmids":["25942693"],"is_preprint":false},{"year":2018,"finding":"K63-linked polyubiquitination of RIG-I by TRIM25 (on 2CARDs) and Riplet (on CTD) positively regulates RIG-I activation; RNF125 mediates K48-linked polyubiquitination leading to proteasomal degradation (negative regulation); CYLD removes K63-linked chains as a negative regulator.","method":"Ubiquitination assays; knockout/knockdown studies; domain-specific ubiquitination mapping","journal":"Frontiers in Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple E3 ligases identified by orthogonal methods, replicated across multiple labs","pmids":["29354136"],"is_preprint":false},{"year":2019,"finding":"NLRP12 dampens RIG-I-mediated signaling by interacting with TRIM25 (via its nucleotide-binding domain) to prevent TRIM25-mediated K63-linked ubiquitination and activation of RIG-I, and by enhancing RNF125-mediated K48-linked degradative ubiquitination of RIG-I.","method":"Co-immunoprecipitation; ubiquitination assays; myeloid-cell-specific Nlrp12 knockout mice; VSV infection assays","journal":"Cell Host & Microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo KO model, multiple orthogonal mechanistic assays","pmids":["30902577"],"is_preprint":false},{"year":2017,"finding":"Upon RIG-I activation, TRIM25 is redistributed into cytoplasmic dots associated with stress granules; RIG-I associates with TRIM25/stress granules and subsequently moves to mitochondrial MAVS; MAVS competes with TRIM25 for RIG-I binding, suggesting RIG-I transits from TRIM25 to MAVS at mitochondria.","method":"Bimolecular fluorescence complementation (BiFC); super-resolution microscopy; subcellular localization studies in virus-infected cells","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, BiFC plus super-resolution, single lab","pmids":["27807226"],"is_preprint":false},{"year":2010,"finding":"SUMOylation of RIG-I by SUMO-1 enhances type I interferon production by increasing K63-linked ubiquitination of RIG-I and promoting its interaction with downstream adaptor Cardif/MAVS.","method":"SUMOylation assay; co-immunoprecipitation; IFN-I production assays","journal":"Protein & Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — biochemical assays identifying new PTM and functional consequence, single lab","pmids":["21203974"],"is_preprint":false},{"year":2018,"finding":"RIG-I uses an ATPase-powered 'kinetic proofreading' mechanism for RNA discrimination: ATP binding facilitates dsRNA engagement but makes RIG-I promiscuous; ATP hydrolysis dissociates self-RNAs faster than 5'ppp dsRNAs; RIG-I translocates directionally from dsRNA end into the stem, with the 5'ppp end throttling translocation to build signaling-active oligomeric complexes.","method":"Transient-state kinetics; ATPase activity assays; translocation assays; helicase motif mutagenesis","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinetic reconstitution with mutagenesis, multiple orthogonal biochemical approaches","pmids":["30270105"],"is_preprint":false},{"year":2019,"finding":"RIG-I is actively antagonized by RNAs containing 5'-monophosphates (5'-p RNA) through a gating mechanism: 5'-p RNA binding induces an alternative RIG-I conformation that blocks the C-terminal domain (CTD), short-circuiting signaling activation.","method":"Quantitative biophysical binding assays; immunological signaling assays; conformational analysis","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biophysical assays plus cellular immunological assays, mechanistic model with multiple orthogonal methods","pmids":["30784585"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of RIG-I in complex with host and viral RNA ligands show that RIG-I adopts two distinct protein folds: a high-affinity signaling-conducive conformation upon binding viral RNA (5'-triphosphate dsRNA), and an autoinhibited conformation upon binding host RNA that stimulates RNA release, explaining selective antiviral sensing.","method":"High-resolution cryo-EM structural determination; functional validation","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple cryo-EM structures with functional validation, mechanistically resolves selectivity mechanism","pmids":["36272408"],"is_preprint":false},{"year":2015,"finding":"RIG-I's selectivity for blunt-ended 5'-ppp dsRNAs is ~3000-fold higher than non-blunt-ended dsRNAs; the autoinhibitory CARD2-HEL2i interface acts as a gate that prevents cellular RNAs from generating productive signaling complexes.","method":"Quantitative binding and ATPase assays; CARD deletion and CARD2-HEL2i interface point mutants; selectivity measurements","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, quantitative mechanistic data","pmids":["26612866"],"is_preprint":false},{"year":2015,"finding":"RIG-I ATPase activity promotes discrimination of self-RNA from non-self-RNA: ATPase activity promotes recycling of RIG-I from self-RNAs (which bind less stably) while non-self 5'ppp dsRNAs resist ATP-driven dissociation; two ribonucleotides at positions 2 and 5 on the bottom strand are minimally required for ATPase stimulation.","method":"In vitro ATPase assays; RNA binding assays; chimeric ribo/deoxyribonucleotide duplexes; IFN-β reporter assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, multiple orthogonal biochemical and cellular assays","pmids":["25736886"],"is_preprint":false},{"year":2018,"finding":"RIG-I Singleton-Merten syndrome variant C268F (in the ATP-binding P-loop) activates signaling independently of ATP but remains RNA-dependent; crystal structure of RIG-I C268F:dsRNA complex shows the mutation induces a structural conformation similar to that induced by ATP, explaining gain-of-function through mimicking the ATP-bound state.","method":"Crystal structure of RIG-I C268F:dsRNA complex; functional signaling assays; ATP-independence experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus functional mutagenesis, mechanistically resolves ATP-independent activation","pmids":["30047865"],"is_preprint":false},{"year":2022,"finding":"Ufmylation promotes RIG-I signaling: UFL1 (E3 ligase for ufmylation) is recruited to 14-3-3ε at ER-mitochondrial contact sites following RNA virus infection; 14-3-3ε undergoes UFM1 conjugation upon RIG-I activation; loss of ufmylation prevents 14-3-3ε interaction with RIG-I and abrogates RIG-I-MAVS interaction and IFN induction.","method":"Protein interaction assays (co-IP); UFM1 conjugation assays; genetic loss-of-function of ufmylation pathway; IFN induction assays","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional KO with IFN readout, multiple components of pathway defined, single lab","pmids":["35394863"],"is_preprint":false},{"year":2021,"finding":"RIG-I is recruited to DNA double-strand breaks (DSBs) and suppresses non-homologous end joining (NHEJ) by interacting with XRCC4 and impeding XRCC4/LIG4/XLF complex formation; conversely, XRCC4 promotes RIG-I signaling by enhancing RIG-I oligomerization and ubiquitination.","method":"Co-immunoprecipitation; DSB recruitment assays; NHEJ repair assays; RIG-I KO and overexpression; in vivo influenza virus infection in XRCC4-silenced mice","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple functional assays, in vivo validation, single lab","pmids":["33846346"],"is_preprint":false},{"year":2018,"finding":"Short triphosphorylated stem-loop RNAs (SLRs, 10-14 bp) specifically activate RIG-I in vivo in mice, inducing type I interferons and ISGs; SLRs demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA (short length precludes oligomerization).","method":"In vivo RNA delivery to mice; RNA sequencing for genome-wide expression; comparison with poly(I:C) which activates multiple sensors","journal":"Science Advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo functional assay with defined synthetic agonists, genome-wide expression profiling, mechanistic conclusion about oligomerization","pmids":["29492454"],"is_preprint":false},{"year":2019,"finding":"MARCH5 (mitochondrial E3 ubiquitin ligase) degrades active RIG-I oligomers via K48-linked polyubiquitination at Lys193 and Lys203 residues of RIG-I; the RING domain of MARCH5 binds to the CARD domain of RIG-I; inactive phosphomimetic RIG-I (S8E) is resistant to MARCH5-mediated degradation.","method":"In vivo ubiquitination assay; co-immunoprecipitation; site-directed mutagenesis; MARCH5 RING domain deletion","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site mapping by mutagenesis, domain interaction defined by Co-IP, single lab","pmids":["31881323"],"is_preprint":false},{"year":2018,"finding":"RIG-I recognizes the 5' region of Dengue virus and Zika virus genomes; affinity purification combined with NGS revealed the 5' end of the DENV genome bearing 5'-triphosphates as the RIG-I ligand during infection.","method":"Affinity purification of RIG-I:RNA complexes; next-generation sequencing; in vitro RNA production and stimulation assays","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RIG-I:RNA pulldown from infected cells with NGS identification, confirmed by in vitro assays","pmids":["29996094"],"is_preprint":false},{"year":2018,"finding":"Nuclear-resident RIG-I senses influenza A virus nuclear replication and cooperates with cytoplasmic RIG-I to induce type I interferon; nuclear RIG-I signals through the canonical RIG-I axis but cannot sense cytoplasmic-replicating Sendai virus, demonstrating compartment-specific sensing.","method":"Live-cell imaging; subcellular fractionation; nuclear RIG-I identification; IAV and SeV infection assays; HBV pregenomic RNA sensing","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, compartment-specific sensing demonstrated, single lab","pmids":["30097581"],"is_preprint":false},{"year":2022,"finding":"RIG-I rapidly and efficiently signals from the constitutively expressed resident pool of receptors without mass aggregation at the mitochondrial membrane; interferon-induced RIG-I protein becomes embedded in cytosolic aggregates that are functionally unrelated to signaling.","method":"Live-cell imaging of RIG-I following dsRNA stimulation; kinetic analysis of signaling complex formation","journal":"Molecular Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional consequence, distinguishes signaling complex from interferon-induced aggregates","pmids":["36521492"],"is_preprint":false},{"year":2020,"finding":"N6-methyladenosine (m6A) modification of viral RNA enables HMPV to escape RIG-I recognition; m6A-deficient virion RNA binds more efficiently to RIG-I, facilitates RIG-I conformational change, and induces higher RIG-I expression and interferon production in a RIG-I-dependent (not MDA5-dependent) manner.","method":"Recombinant HMPV with m6A site mutations; RNA pulldown/binding assays; conformational assays; RIG-I KO cell lines; in vivo cotton rat infection","journal":"Nature Microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assays, genetic KO cells, in vivo model, multiple orthogonal methods","pmids":["32015498"],"is_preprint":false},{"year":2019,"finding":"USP14 deubiquitinates K63-linked polyubiquitin chains from RIG-I, negatively regulating antiviral responses; USP14 directly interacts with RIG-I and its knockdown enhances RIG-I-triggered type I IFN signaling.","method":"Co-immunoprecipitation; in vitro deubiquitination assay; siRNA knockdown; USP14-specific inhibitor (IU1) in vitro and in vivo","journal":"European Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct deubiquitination assay, Co-IP, multiple cell types and in vivo validation, single lab","pmids":["30466171"],"is_preprint":false},{"year":2020,"finding":"USP27X removes K63-linked polyubiquitin chains from RIG-I in a deubiquitinase-dependent manner to negatively regulate RIG-I-mediated antiviral signaling.","method":"siRNA library screening; co-immunoprecipitation; deubiquitination assays; overexpression and knockdown of USP27X","journal":"PLoS Pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assays with Co-IP, functional signaling assays, single lab","pmids":["32027733"],"is_preprint":false},{"year":2019,"finding":"LRRC59 positively regulates RIG-I (DDX58) signaling by interacting with ISG15-associated RIG-I and blocking its association with LRRC25 (the secondary receptor that delivers RIG-I to autophagosomes for SQSTM1/p62-dependent degradation), thereby preventing autophagic degradation of RIG-I.","method":"Co-immunoprecipitation; autophagy flux assays; KO cells; IFN signaling measurements","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO functional assay, pathway placement, single lab","pmids":["31068071"],"is_preprint":false},{"year":2017,"finding":"Zyxin stabilizes physical interactions between RIG-I (and MDA5) and MAVS, functioning as a scaffold; zyxin co-immunoprecipitates with MAVS and co-localizes on mitochondria; ZYX knockdown abolishes RLR-MAVS interactions and attenuates IFN-β production.","method":"Yeast two-hybrid screening; co-immunoprecipitation; proximity ligation assay; ZYX knockdown with IFN-β reporter; influenza A virus RNA stimulation","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, proximity ligation, functional knockdown, single lab","pmids":["28928438"],"is_preprint":false},{"year":2021,"finding":"IFI16 binds to influenza viral RNA via its HINa domain and to RIG-I protein via its PYRIN domain, promoting IAV-induced K63-linked polyubiquitination and RIG-I activation; IFI16 also upregulates RIG-I transcription by directly binding to and recruiting RNA polymerase II to the RIG-I promoter.","method":"IFI16 KO cells and p204-deficient mice; domain-specific binding assays; K63 ubiquitination assay; RNA Pol II ChIP; IFN-I production assays","journal":"Nature Microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model plus domain-specific binding assays plus ubiquitination assay, multiple orthogonal methods","pmids":["33986530"],"is_preprint":false},{"year":2022,"finding":"JMJD4 demethylates RIG-I at constitutively methylated residues K18 and K146; demethylated RIG-I suppresses IL-6-STAT3 signaling; methylated RIG-I associates with AMPKα to inhibit HMGCR phosphorylation, promoting HMGCR enzymatic activity and cholesterol synthesis.","method":"Mass spectrometry identification of methylation sites; hepatocyte-specific RIG-I KO mice; specific antibodies against methylated lysine sites; RIG-I lysine mutant mice; functional signaling assays","journal":"Journal of Hematology & Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified PTM with KO mice and mutant mice, multiple functional readouts, single lab","pmids":["36333807"],"is_preprint":false},{"year":2021,"finding":"Novel DDX58 variant R109C is a gain-of-function mutation causing lupus nephritis through reduced RIG-I autoinhibition, leading to RIG-I hyperactivation, increased K63 ubiquitination, and MAVS aggregation; JAK inhibitor therapy suppressed the elevated IFN signature.","method":"Whole-exome sequencing; biochemical IFN signaling assays; K63 ubiquitination assay; MAVS aggregation assay; single-cell RNA sequencing","journal":"JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function biochemical assays with multiple mechanistic readouts, single lab, novel variant","pmids":["36261300"],"is_preprint":false},{"year":2020,"finding":"DUSP11 (RNA triphosphatase) removes 5'-triphosphates from both host and virus-derived RNAs, rendering them less active in inducing RIG-I-mediated immune responses; DUSP11 deficiency results in higher proportions of triphosphorylated viral transcripts, enhanced RIG-I activation, and attenuated virus replication rescued by RIG-I knockdown.","method":"DUSP11 knockdown/KO cells and mice; viral triphosphate RNA profiling; RIG-I activation assays; genetic rescue experiments","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular mechanism (triphosphate removal), in vivo mouse model, genetic rescue confirms RIG-I specificity","pmids":["33184222"],"is_preprint":false},{"year":2023,"finding":"CD97 negatively regulates RIG-I by upregulating RNF125 expression, which induces RNF125-mediated K48-linked ubiquitination of RIG-I at Lys181, leading to proteasomal degradation of RIG-I and suppression of IFN-I signaling.","method":"Co-immunoprecipitation; ubiquitination site mutagenesis; CD97-deficient mice; IFN-I signaling assays; VSV and SARS-CoV-2 replication assays","journal":"Cellular & Molecular Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site mapping, Co-IP, in vivo KO model, single lab","pmids":["37978243"],"is_preprint":false},{"year":2023,"finding":"RIG-I competes with SPOP to bind PD-L1, attenuating polyubiquitination and proteasomal degradation of PD-L1, thereby promoting PD-L1 stability and colon cancer immune evasion independently of type I interferon stimulation.","method":"Co-immunoprecipitation; ubiquitination assays; RIG-I knockdown/overexpression; in vivo tumor models","journal":"Journal for Immunotherapy of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing competition, ubiquitination assays, in vivo validation, single lab","pmids":["37758653"],"is_preprint":false},{"year":2012,"finding":"ATP and dsRNA binding triggers dimerization of RIG-I with conformational rearrangements exposing the tandem CARD domains; full-length RIG-I forms a 2:2 complex with dsRNA; phosphorylation-mimicking mutants S8E and T170E impair RIG-I binding to TRIM25, unanchored K63-linked polyubiquitin, and MAVS.","method":"Electron microscopy of RIG-I:dsRNA complex; co-immunoprecipitation; biochemical binding assays; phosphomimetic mutagenesis","journal":"Protein & Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EM structure plus mutagenesis and Co-IP, multiple orthogonal methods, single lab","pmids":["23264040"],"is_preprint":false},{"year":2023,"finding":"RIG-I recognizes metabolite-capped RNAs (NAD+, FAD, dephosphoCoA caps) as signaling ligands; these RNAs have high affinity for RIG-I, stimulate ATPase activity comparably to 5'ppp dsRNA, and activate innate antiviral signaling in cells.","method":"In vitro transcription with metabolite initiators; ATPase activity assays; binding assays; cellular IFN signaling assays","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution plus cellular assays, novel ligand class established, single lab","pmids":["37326006"],"is_preprint":false},{"year":2023,"finding":"RIG-I bound to long dsRNA (>500 bp) with slow kinetics, forming stable complexes that did not dissociate; short dsRNA (<500 bp) formed complexes that dissociated efficiently in an ATP hydrolysis-dependent manner; dissociated RIG-I underwent homo-oligomerization acquiring ability to associate with MAVS, explaining length-dependent signaling.","method":"Binding kinetics assays; ATP hydrolysis assays; RIG-I oligomerization assays; MAVS association assays; biological activity in living cells","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinetic and biochemical assays, mechanistic model for length discrimination, single lab","pmids":["37072508"],"is_preprint":false},{"year":2022,"finding":"SMS-associated RIG-I mutations (E510V and Q517H) cause a loosened latch-gate engagement in apo RIG-I (in the HEL2i domain), dampening ATPase activity and impairing self-RNA (Cap2 moiety) proofreading, leading to increased immune activation.","method":"Hydrogen/deuterium exchange mass spectrometry (HDX-MS); single molecule magnetic tweezers (MT); ATPase assays; RNA proofreading assays","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple structural/biophysical methods (HDX-MS + single molecule MT) with functional validation, mechanistic explanation for SMS variants","pmids":["35580046"],"is_preprint":false}],"current_model":"RIG-I (DDX58) is a cytoplasmic DExD/H-box RNA helicase that functions as an innate immune pattern recognition receptor by directly binding 5'-triphosphate blunt-ended dsRNA from RNA viruses; upon RNA binding, RIG-I undergoes ATP-dependent conformational changes and kinetic proofreading (ATP hydrolysis discriminates self from non-self RNA), releases its autoinhibited tandem CARD domains, which are activated by K63-linked polyubiquitination (by TRIM25 on CARDs and Riplet on CTD) and form a homo-tetrameric lock-washer structure that nucleates MAVS filament formation on mitochondria, triggering downstream IRF3 and NF-κB activation to induce type I interferons; this signaling is tightly regulated by multiple PTMs (K48-linked ubiquitination by RNF125/MARCH5 for degradation, SUMOylation, methylation, phosphorylation, ufmylation) and by deubiquitinases (CYLD, USP14, USP27X), and gain-of-function mutations in ATP-binding motifs cause constitutive activation leading to interferonopathies including atypical Singleton-Merten syndrome and lupus nephritis."},"narrative":{"mechanistic_narrative":"RIG-I (DDX58) is a cytoplasmic RNA helicase that functions as a pattern-recognition receptor for the innate antiviral response, providing essential, non-redundant detection of distinct RNA virus classes including paramyxoviruses, influenza, flaviviruses, and Japanese encephalitis virus to drive IRF3-dependent type I interferon induction [PMID:16625202, PMID:16039576, PMID:29996094]. Its activating ligand is RNA bearing a 5'-triphosphate end generated by viral polymerases, with physiological agonists corresponding to full-length 5'-triphosphate viral genomes rather than capped or modified RNA [PMID:17038590, PMID:20144762]. Structurally, RIG-I sheathes dsRNA across helicase domains HEL1/HEL2, the HEL2i insertion, and a C-terminal regulatory domain, with cryo-EM showing it can adopt either a signaling-conducive fold on viral 5'-triphosphate dsRNA or an autoinhibited fold on host RNA that triggers RNA release [PMID:22000018, PMID:36272408]. Self/non-self discrimination is enforced by an ATPase-powered kinetic-proofreading mechanism in which ATP hydrolysis dissociates self-RNAs faster than blunt-ended 5'-triphosphate dsRNA, conferring ~3000-fold selectivity gated by the autoinhibitory CARD2-HEL2i interface [PMID:30270105, PMID:26612866, PMID:25736886]. Productive RNA engagement releases the tandem CARDs, which must homo-tetramerize into a lock-washer configuration—stabilized by TRIM25-mediated K63 polyubiquitination—to nucleate MAVS filament formation on mitochondria and propagate signaling [PMID:25942693, PMID:23264040]. Signaling output is tuned by an extensive PTM network: positive regulation through K63 ubiquitination (TRIM25, Riplet), SUMOylation, and ufmylation, and negative regulation through K48-linked degradative ubiquitination (RNF125, MARCH5), deubiquitination (CYLD, USP14, USP27X), and autophagic turnover [PMID:29354136, PMID:21203974, PMID:35394863, PMID:31881323, PMID:30466171, PMID:32027733, PMID:31068071]. Gain-of-function mutations in the ATP-binding and latch-gate regions cause constitutive activation: C268F and E373A produce atypical Singleton-Merten syndrome, latch-gate variants impair proofreading, and R109C causes lupus nephritis via reduced autoinhibition [PMID:25620203, PMID:30047865, PMID:36261300, PMID:35580046].","teleology":[{"year":2006,"claim":"Established that RIG-I is a genuine, non-redundant antiviral sensor and defined its division of labor with MDA5 across virus classes, settling which receptor detects which pathogens.","evidence":"RIG-I and MDA5 knockout mice with viral challenge and interferon induction assays, plus cell-type-specific IRF3/IKK pathway placement","pmids":["16625202","16039576"],"confidence":"High","gaps":["Did not identify the molecular ligand recognized","Did not resolve the structural basis of recognition"]},{"year":2006,"claim":"Identified the activating ligand as 5'-triphosphate RNA, defining the molecular signature that distinguishes viral from host RNA.","evidence":"Direct binding of 5'-triphosphate RNA to RIG-I with phosphatase-sensitivity controls and IFN-alpha assays","pmids":["17038590"],"confidence":"High","gaps":["Did not establish which authentic viral RNA species act as agonists during infection","Did not address dsRNA end structure or length requirements"]},{"year":2010,"claim":"Defined the bona fide physiological agonists in infected cells as full-length 5'-triphosphate viral genomes, ruling out transcripts and cleaved self-RNA, and demonstrated a SUMOylation positive-regulation arm.","evidence":"Orthogonal RNA-IP, fractionation and genetic approaches in infected cells; SUMOylation and Co-IP assays","pmids":["20144762","21203974"],"confidence":"High","gaps":["Did not explain how blunt-end and length selectivity are mechanistically achieved","SUMOylation findings from a single lab"]},{"year":2011,"claim":"Resolved the domain architecture coupling RNA recognition to ATP hydrolysis, providing the structural framework for activation.","evidence":"X-ray crystallography of the RIG-I:dsRNA complex defining HEL1/HEL2/HEL2i, CTD and pincer","pmids":["22000018"],"confidence":"High","gaps":["Static structure did not capture the autoinhibited apo state or signaling conformation","Did not show CARD oligomerization mechanism"]},{"year":2012,"claim":"Linked ATP/dsRNA binding to conformational CARD exposure and dimerization, and showed phosphorylation as a brake on TRIM25/ubiquitin/MAVS engagement.","evidence":"Electron microscopy of RIG-I:dsRNA 2:2 complex with phosphomimetic mutagenesis and Co-IP","pmids":["23264040"],"confidence":"Medium","gaps":["EM resolution limited; single lab","Did not resolve the active CARD tetramer geometry"]},{"year":2015,"claim":"Defined the biochemical basis of self/non-self discrimination: ATPase-driven recycling from self-RNA, blunt-end selectivity, and the CARD2-HEL2i autoinhibitory gate; CARD tetramerization shown as prerequisite for MAVS nucleation.","evidence":"Quantitative ATPase/binding assays, chimeric duplexes, interface mutants, IFN-beta reporters; structural/biochemical reconstitution of CARD oligomerization","pmids":["26612866","25736886","25942693"],"confidence":"High","gaps":["Did not capture the full kinetic trajectory of proofreading","CARD tetramer model partly from review synthesis"]},{"year":2015,"claim":"Demonstrated that constitutive RIG-I activation causes human interferonopathy, establishing RIG-I gain-of-function as a disease mechanism.","evidence":"Exome sequencing of Singleton-Merten families with C268F/E373A; IFN activity and ISG assays plus structural context","pmids":["25620203"],"confidence":"High","gaps":["Did not structurally resolve how the mutations mimic activation","Limited to two families"]},{"year":2018,"claim":"Resolved the kinetic-proofreading and translocation logic of RNA discrimination and the structural basis of ATP-independent gain-of-function activation.","evidence":"Transient-state kinetics and translocation assays with helicase mutants; crystal structure of the C268F:dsRNA complex","pmids":["30270105","30047865"],"confidence":"High","gaps":["Did not address how host RNA conformation differs structurally","In vitro kinetics not directly mapped onto in-cell signaling timing"]},{"year":2018,"claim":"Expanded the ligand repertoire to flaviviral genome 5' ends, established that short stem-loop RNAs activate without oligomerization, and detailed the PTM regulatory network.","evidence":"Affinity purification with NGS of DENV/ZIKV ligands; in vivo SLR delivery with RNA-seq; review of TRIM25/Riplet/RNF125/CYLD ubiquitin regulation","pmids":["29996094","29492454","29354136"],"confidence":"High","gaps":["Reconciling oligomerization-independent short-RNA signaling with filament models","Ubiquitin regulators summarized rather than newly reconstituted here"]},{"year":2019,"claim":"Defined multiple negative and positive regulators acting on RIG-I ubiquitination, antagonist RNA gating, and antagonist RNA conformational suppression.","evidence":"NLRP12-TRIM25 Co-IP with KO mice; USP14 deubiquitination; LRRC59/autophagy assays; biophysical 5'-monophosphate gating assays","pmids":["30902577","30466171","31068071","30784585"],"confidence":"High","gaps":["Hierarchy and temporal order among regulators unresolved","Several regulator findings from single labs"]},{"year":2020,"claim":"Established control of RIG-I activity at the level of ligand 5'-phosphate state and viral m6A modification as immune-escape strategies, plus additional DUB and ubiquitin regulators.","evidence":"DUSP11 triphosphatase KO with genetic rescue; recombinant m6A-mutant HMPV binding/conformation assays; USP27X DUB assays; MARCH5 K48 ubiquitination site mapping","pmids":["33184222","32015498","32027733","31881323"],"confidence":"High","gaps":["Quantitative contribution of each escape route in natural infection unknown","Several mechanisms validated in single labs"]},{"year":2021,"claim":"Uncovered non-canonical and compartment-specific roles: nuclear RIG-I sensing, IFI16-mediated transcriptional and ubiquitin co-activation, an NHEJ-suppressive role at DNA breaks, and a second interferonopathy mutation.","evidence":"Subcellular fractionation/imaging of nuclear RIG-I; IFI16 KO mice with domain-specific binding and ChIP; XRCC4 Co-IP and NHEJ/repair assays; exome sequencing of R109C lupus nephritis","pmids":["30097581","33986530","33846346","36261300"],"confidence":"Medium","gaps":["Mechanism of nuclear RIG-I import and signaling unclear","DNA-break role mostly single-lab","R109C variant from single family"]},{"year":2022,"claim":"Resolved the conformational selectivity switch by cryo-EM, defined latch-gate proofreading defects in disease, established ufmylation as a positive arm, refined the resident-pool signaling model, and identified a lysine-methylation/metabolic axis.","evidence":"Cryo-EM of RIG-I with viral vs host RNA; HDX-MS and single-molecule tweezers on SMS latch-gate variants; UFL1/14-3-3-epsilon ufmylation assays; live-cell imaging of resident signaling pool; JMJD4 demethylation with KO mice","pmids":["36272408","35580046","35394863","36521492","36333807"],"confidence":"High","gaps":["Relationship between resident-pool signaling and prior filament/oligomer models incompletely unified","Metabolic and ufmylation arms from single labs"]},{"year":2023,"claim":"Broadened the ligand spectrum to metabolite-capped RNAs, defined length-dependent dissociation kinetics governing oligomerization, and revealed interferon-independent roles in PD-L1 stabilization and additional ubiquitin-mediated negative regulation.","evidence":"In vitro transcription with metabolite caps and ATPase/IFN assays; binding-kinetics/oligomerization assays on long vs short dsRNA; PD-L1/SPOP competition and tumor models; CD97-RNF125 K48 ubiquitination with KO mice","pmids":["37326006","37072508","37758653","37978243"],"confidence":"Medium","gaps":["Physiological prevalence of metabolite-capped RNA ligands unknown","Interferon-independent tumor role from single lab"]},{"year":null,"claim":"How the diverse activation modes—oligomerization-independent short-RNA signaling, resident-pool signaling, and filament nucleation—are integrated into a single in-cell signaling pathway remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling short-RNA, resident-pool and filament data","Temporal hierarchy of positive and negative PTM regulators undefined","In-cell structure of the active CARD-MAVS interface not directly resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3,13,21,36]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,11,15,16,37]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[11,15,37]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1,11,13,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,22,23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6,9,17,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,18]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,13,35]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,16,31,38]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18]}],"complexes":[],"partners":["MAVS","TRIM25","RNF125","MARCH5","USP14","XRCC4","ZYX","NLRP12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95786","full_name":"Antiviral innate immune response receptor RIG-I","aliases":["ATP-dependent RNA helicase DDX58","DEAD box protein 58","RIG-I-like receptor 1","RLR-1","RNA sensor RIG-I","Retinoic acid-inducible gene 1 protein","RIG-1","Retinoic acid-inducible gene I protein","RIG-I"],"length_aa":925,"mass_kda":106.6,"function":"Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines (PubMed:15208624, PubMed:15708988, PubMed:16125763, PubMed:16127453, PubMed:16153868, PubMed:17190814, PubMed:18636086, PubMed:19122199, PubMed:19211564, PubMed:24366338, PubMed:28469175, PubMed:29117565, PubMed:31006531, PubMed:34935440, PubMed:35263596, PubMed:36793726). Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments (PubMed:15208624, PubMed:15708988). The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531). Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length) (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV) (PubMed:21616437, PubMed:21884169). It also detects rotaviruses and reoviruses (PubMed:21616437, PubMed:21884169). Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.74). Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV) (PubMed:19631370). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration","subcellular_location":"Cytoplasm; Cell projection, ruffle membrane; Cytoplasm, cytoskeleton; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/O95786/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RIGI","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RIGI","total_profiled":1310},"omim":[{"mim_id":"621401","title":"DEAH-BOX HELICASE 35; DHX35","url":"https://www.omim.org/entry/621401"},{"mim_id":"620004","title":"NMRA-LIKE REDOX SENSOR 1; NMRAL1","url":"https://www.omim.org/entry/620004"},{"mim_id":"619773","title":"IMMUNODEFICIENCY 95; IMD95","url":"https://www.omim.org/entry/619773"},{"mim_id":"619410","title":"TUBULIN TYROSINE LIGASE-LIKE 12; TTLL12","url":"https://www.omim.org/entry/619410"},{"mim_id":"619117","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 16; ARL16","url":"https://www.omim.org/entry/619117"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RIGI"},"hgnc":{"alias_symbol":["RIG-I","FLJ13599","DKFZp434J1111","RIG-1","RIG1"],"prev_symbol":["DDX58"]},"alphafold":{"accession":"O95786","domains":[{"cath_id":"1.10.533.10","chopping":"2-92","consensus_level":"medium","plddt":89.312,"start":2,"end":92},{"cath_id":"1.10.533.10","chopping":"95-184","consensus_level":"medium","plddt":89.3291,"start":95,"end":184},{"cath_id":"3.40.50.300","chopping":"244-450","consensus_level":"high","plddt":90.637,"start":244,"end":450},{"cath_id":"3.40.50.300","chopping":"456-461_608-743","consensus_level":"high","plddt":82.1634,"start":456,"end":743},{"cath_id":"1.20.1320.30","chopping":"471-599","consensus_level":"high","plddt":88.7788,"start":471,"end":599},{"cath_id":"2.170.150.30","chopping":"805-922","consensus_level":"high","plddt":86.5275,"start":805,"end":922}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95786","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95786-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95786-F1-predicted_aligned_error_v6.png","plddt_mean":85.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RIGI","jax_strain_url":"https://www.jax.org/strain/search?query=RIGI"},"sequence":{"accession":"O95786","fasta_url":"https://rest.uniprot.org/uniprotkb/O95786.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95786/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95786"}},"corpus_meta":[{"pmid":"16625202","id":"PMC_16625202","title":"Differential 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\"Gene-targeted RIG-I knockout and MDA5 knockout mice; interferon induction assays; viral challenge experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype, replicated across multiple virus families and two independent KO models\",\n      \"pmids\": [\"16625202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"5'-triphosphate RNA (3pRNA) is the molecular ligand for RIG-I; the 5'-triphosphate end generated by viral polymerases directly binds RIG-I and activates interferon responses, whereas capping or nucleoside modification of the 5'-triphosphate abrogates detection.\",\n      \"method\": \"Direct binding assay (5'-triphosphate RNA to RIG-I); phosphatase sensitivity assay; genomic RNA from negative-strand RNA viruses; interferon-alpha response assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding demonstrated, phosphatase sensitivity controls, replicated across multiple labs subsequently\",\n      \"pmids\": [\"17038590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RIG-I is required for induction of type I interferons via IRF3 activation through IκB kinase-related kinases in fibroblasts and conventional dendritic cells after RNA virus infection; plasmacytoid DCs use the TLR system rather than RIG-I for viral detection.\",\n      \"method\": \"Gene-targeted RIG-I knockout mice; IFN induction assays; cell-type-specific analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cell-type-specific phenotype, pathway placement via IRF3 and IKK-related kinases\",\n      \"pmids\": [\"16039576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of RIG-I in complex with dsRNA reveals that dsRNA is sheathed within a network including helicase domains HEL1 and HEL2, an insertion domain HEL2i, and a C-terminal regulatory domain (CTD); a V-shaped pincer connects HEL2 and CTD, coupling RNA binding with ATP hydrolysis.\",\n      \"method\": \"X-ray crystallography of RIG-I:dsRNA complex\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional domain architecture fully resolved\",\n      \"pmids\": [\"22000018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Physiological RIG-I agonists during influenza A virus or Sendai virus infection are exclusively generated by virus replication and correspond to full-length virus genomes bearing 5'-triphosphates; non-genomic viral transcripts, short replication intermediates, and cleaved self-RNA do not substantially contribute to interferon induction.\",\n      \"method\": \"Three orthogonal approaches (RNA immunoprecipitation, biochemical fractionation, genetic approaches) to identify RIG-I agonists in infected cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, two virus systems, rigorous controls\",\n      \"pmids\": [\"20144762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDX58 (RIG-I) mutations in ATP-binding motifs (C268F and E373A) confer constitutive RIG-I activation and cause atypical Singleton-Merten syndrome with increased interferon activity and IFN-stimulated gene expression; C268 and E373 residues are located close to ADP and RNA binding sites.\",\n      \"method\": \"Exome sequencing; functional assays measuring IFN activity and ISG expression; structural analysis of mutant positions; cytopathic assays in human trabecular meshwork cells\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function mutagenesis with IFN activity assays, structural context, disease-linked mutations in two independent families\",\n      \"pmids\": [\"25620203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RIG-I CARDs must form homo-tetramers (lock-washer configuration) to interact with MAVS and nucleate MAVS filament formation, which is a prerequisite for downstream signaling; TRIM25-mediated K63-linked polyubiquitination stabilizes the 2CARD tetramer.\",\n      \"method\": \"Structural analysis; biochemical reconstitution of CARD oligomerization; MAVS filament formation assays\",\n      \"journal\": \"Current Opinion in Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review summarizing reconstitution and structural data from primary papers; mechanistic model supported by biochemical evidence\",\n      \"pmids\": [\"25942693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"K63-linked polyubiquitination of RIG-I by TRIM25 (on 2CARDs) and Riplet (on CTD) positively regulates RIG-I activation; RNF125 mediates K48-linked polyubiquitination leading to proteasomal degradation (negative regulation); CYLD removes K63-linked chains as a negative regulator.\",\n      \"method\": \"Ubiquitination assays; knockout/knockdown studies; domain-specific ubiquitination mapping\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple E3 ligases identified by orthogonal methods, replicated across multiple labs\",\n      \"pmids\": [\"29354136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NLRP12 dampens RIG-I-mediated signaling by interacting with TRIM25 (via its nucleotide-binding domain) to prevent TRIM25-mediated K63-linked ubiquitination and activation of RIG-I, and by enhancing RNF125-mediated K48-linked degradative ubiquitination of RIG-I.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays; myeloid-cell-specific Nlrp12 knockout mice; VSV infection assays\",\n      \"journal\": \"Cell Host & Microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo KO model, multiple orthogonal mechanistic assays\",\n      \"pmids\": [\"30902577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Upon RIG-I activation, TRIM25 is redistributed into cytoplasmic dots associated with stress granules; RIG-I associates with TRIM25/stress granules and subsequently moves to mitochondrial MAVS; MAVS competes with TRIM25 for RIG-I binding, suggesting RIG-I transits from TRIM25 to MAVS at mitochondria.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC); super-resolution microscopy; subcellular localization studies in virus-infected cells\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, BiFC plus super-resolution, single lab\",\n      \"pmids\": [\"27807226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SUMOylation of RIG-I by SUMO-1 enhances type I interferon production by increasing K63-linked ubiquitination of RIG-I and promoting its interaction with downstream adaptor Cardif/MAVS.\",\n      \"method\": \"SUMOylation assay; co-immunoprecipitation; IFN-I production assays\",\n      \"journal\": \"Protein & Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — biochemical assays identifying new PTM and functional consequence, single lab\",\n      \"pmids\": [\"21203974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RIG-I uses an ATPase-powered 'kinetic proofreading' mechanism for RNA discrimination: ATP binding facilitates dsRNA engagement but makes RIG-I promiscuous; ATP hydrolysis dissociates self-RNAs faster than 5'ppp dsRNAs; RIG-I translocates directionally from dsRNA end into the stem, with the 5'ppp end throttling translocation to build signaling-active oligomeric complexes.\",\n      \"method\": \"Transient-state kinetics; ATPase activity assays; translocation assays; helicase motif mutagenesis\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinetic reconstitution with mutagenesis, multiple orthogonal biochemical approaches\",\n      \"pmids\": [\"30270105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RIG-I is actively antagonized by RNAs containing 5'-monophosphates (5'-p RNA) through a gating mechanism: 5'-p RNA binding induces an alternative RIG-I conformation that blocks the C-terminal domain (CTD), short-circuiting signaling activation.\",\n      \"method\": \"Quantitative biophysical binding assays; immunological signaling assays; conformational analysis\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biophysical assays plus cellular immunological assays, mechanistic model with multiple orthogonal methods\",\n      \"pmids\": [\"30784585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of RIG-I in complex with host and viral RNA ligands show that RIG-I adopts two distinct protein folds: a high-affinity signaling-conducive conformation upon binding viral RNA (5'-triphosphate dsRNA), and an autoinhibited conformation upon binding host RNA that stimulates RNA release, explaining selective antiviral sensing.\",\n      \"method\": \"High-resolution cryo-EM structural determination; functional validation\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple cryo-EM structures with functional validation, mechanistically resolves selectivity mechanism\",\n      \"pmids\": [\"36272408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RIG-I's selectivity for blunt-ended 5'-ppp dsRNAs is ~3000-fold higher than non-blunt-ended dsRNAs; the autoinhibitory CARD2-HEL2i interface acts as a gate that prevents cellular RNAs from generating productive signaling complexes.\",\n      \"method\": \"Quantitative binding and ATPase assays; CARD deletion and CARD2-HEL2i interface point mutants; selectivity measurements\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, quantitative mechanistic data\",\n      \"pmids\": [\"26612866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RIG-I ATPase activity promotes discrimination of self-RNA from non-self-RNA: ATPase activity promotes recycling of RIG-I from self-RNAs (which bind less stably) while non-self 5'ppp dsRNAs resist ATP-driven dissociation; two ribonucleotides at positions 2 and 5 on the bottom strand are minimally required for ATPase stimulation.\",\n      \"method\": \"In vitro ATPase assays; RNA binding assays; chimeric ribo/deoxyribonucleotide duplexes; IFN-β reporter assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, multiple orthogonal biochemical and cellular assays\",\n      \"pmids\": [\"25736886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RIG-I Singleton-Merten syndrome variant C268F (in the ATP-binding P-loop) activates signaling independently of ATP but remains RNA-dependent; crystal structure of RIG-I C268F:dsRNA complex shows the mutation induces a structural conformation similar to that induced by ATP, explaining gain-of-function through mimicking the ATP-bound state.\",\n      \"method\": \"Crystal structure of RIG-I C268F:dsRNA complex; functional signaling assays; ATP-independence experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus functional mutagenesis, mechanistically resolves ATP-independent activation\",\n      \"pmids\": [\"30047865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ufmylation promotes RIG-I signaling: UFL1 (E3 ligase for ufmylation) is recruited to 14-3-3ε at ER-mitochondrial contact sites following RNA virus infection; 14-3-3ε undergoes UFM1 conjugation upon RIG-I activation; loss of ufmylation prevents 14-3-3ε interaction with RIG-I and abrogates RIG-I-MAVS interaction and IFN induction.\",\n      \"method\": \"Protein interaction assays (co-IP); UFM1 conjugation assays; genetic loss-of-function of ufmylation pathway; IFN induction assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional KO with IFN readout, multiple components of pathway defined, single lab\",\n      \"pmids\": [\"35394863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RIG-I is recruited to DNA double-strand breaks (DSBs) and suppresses non-homologous end joining (NHEJ) by interacting with XRCC4 and impeding XRCC4/LIG4/XLF complex formation; conversely, XRCC4 promotes RIG-I signaling by enhancing RIG-I oligomerization and ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation; DSB recruitment assays; NHEJ repair assays; RIG-I KO and overexpression; in vivo influenza virus infection in XRCC4-silenced mice\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple functional assays, in vivo validation, single lab\",\n      \"pmids\": [\"33846346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Short triphosphorylated stem-loop RNAs (SLRs, 10-14 bp) specifically activate RIG-I in vivo in mice, inducing type I interferons and ISGs; SLRs demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA (short length precludes oligomerization).\",\n      \"method\": \"In vivo RNA delivery to mice; RNA sequencing for genome-wide expression; comparison with poly(I:C) which activates multiple sensors\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo functional assay with defined synthetic agonists, genome-wide expression profiling, mechanistic conclusion about oligomerization\",\n      \"pmids\": [\"29492454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MARCH5 (mitochondrial E3 ubiquitin ligase) degrades active RIG-I oligomers via K48-linked polyubiquitination at Lys193 and Lys203 residues of RIG-I; the RING domain of MARCH5 binds to the CARD domain of RIG-I; inactive phosphomimetic RIG-I (S8E) is resistant to MARCH5-mediated degradation.\",\n      \"method\": \"In vivo ubiquitination assay; co-immunoprecipitation; site-directed mutagenesis; MARCH5 RING domain deletion\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site mapping by mutagenesis, domain interaction defined by Co-IP, single lab\",\n      \"pmids\": [\"31881323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RIG-I recognizes the 5' region of Dengue virus and Zika virus genomes; affinity purification combined with NGS revealed the 5' end of the DENV genome bearing 5'-triphosphates as the RIG-I ligand during infection.\",\n      \"method\": \"Affinity purification of RIG-I:RNA complexes; next-generation sequencing; in vitro RNA production and stimulation assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RIG-I:RNA pulldown from infected cells with NGS identification, confirmed by in vitro assays\",\n      \"pmids\": [\"29996094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nuclear-resident RIG-I senses influenza A virus nuclear replication and cooperates with cytoplasmic RIG-I to induce type I interferon; nuclear RIG-I signals through the canonical RIG-I axis but cannot sense cytoplasmic-replicating Sendai virus, demonstrating compartment-specific sensing.\",\n      \"method\": \"Live-cell imaging; subcellular fractionation; nuclear RIG-I identification; IAV and SeV infection assays; HBV pregenomic RNA sensing\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, compartment-specific sensing demonstrated, single lab\",\n      \"pmids\": [\"30097581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RIG-I rapidly and efficiently signals from the constitutively expressed resident pool of receptors without mass aggregation at the mitochondrial membrane; interferon-induced RIG-I protein becomes embedded in cytosolic aggregates that are functionally unrelated to signaling.\",\n      \"method\": \"Live-cell imaging of RIG-I following dsRNA stimulation; kinetic analysis of signaling complex formation\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional consequence, distinguishes signaling complex from interferon-induced aggregates\",\n      \"pmids\": [\"36521492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"N6-methyladenosine (m6A) modification of viral RNA enables HMPV to escape RIG-I recognition; m6A-deficient virion RNA binds more efficiently to RIG-I, facilitates RIG-I conformational change, and induces higher RIG-I expression and interferon production in a RIG-I-dependent (not MDA5-dependent) manner.\",\n      \"method\": \"Recombinant HMPV with m6A site mutations; RNA pulldown/binding assays; conformational assays; RIG-I KO cell lines; in vivo cotton rat infection\",\n      \"journal\": \"Nature Microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assays, genetic KO cells, in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"32015498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP14 deubiquitinates K63-linked polyubiquitin chains from RIG-I, negatively regulating antiviral responses; USP14 directly interacts with RIG-I and its knockdown enhances RIG-I-triggered type I IFN signaling.\",\n      \"method\": \"Co-immunoprecipitation; in vitro deubiquitination assay; siRNA knockdown; USP14-specific inhibitor (IU1) in vitro and in vivo\",\n      \"journal\": \"European Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct deubiquitination assay, Co-IP, multiple cell types and in vivo validation, single lab\",\n      \"pmids\": [\"30466171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP27X removes K63-linked polyubiquitin chains from RIG-I in a deubiquitinase-dependent manner to negatively regulate RIG-I-mediated antiviral signaling.\",\n      \"method\": \"siRNA library screening; co-immunoprecipitation; deubiquitination assays; overexpression and knockdown of USP27X\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assays with Co-IP, functional signaling assays, single lab\",\n      \"pmids\": [\"32027733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRRC59 positively regulates RIG-I (DDX58) signaling by interacting with ISG15-associated RIG-I and blocking its association with LRRC25 (the secondary receptor that delivers RIG-I to autophagosomes for SQSTM1/p62-dependent degradation), thereby preventing autophagic degradation of RIG-I.\",\n      \"method\": \"Co-immunoprecipitation; autophagy flux assays; KO cells; IFN signaling measurements\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO functional assay, pathway placement, single lab\",\n      \"pmids\": [\"31068071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Zyxin stabilizes physical interactions between RIG-I (and MDA5) and MAVS, functioning as a scaffold; zyxin co-immunoprecipitates with MAVS and co-localizes on mitochondria; ZYX knockdown abolishes RLR-MAVS interactions and attenuates IFN-β production.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation; proximity ligation assay; ZYX knockdown with IFN-β reporter; influenza A virus RNA stimulation\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, proximity ligation, functional knockdown, single lab\",\n      \"pmids\": [\"28928438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFI16 binds to influenza viral RNA via its HINa domain and to RIG-I protein via its PYRIN domain, promoting IAV-induced K63-linked polyubiquitination and RIG-I activation; IFI16 also upregulates RIG-I transcription by directly binding to and recruiting RNA polymerase II to the RIG-I promoter.\",\n      \"method\": \"IFI16 KO cells and p204-deficient mice; domain-specific binding assays; K63 ubiquitination assay; RNA Pol II ChIP; IFN-I production assays\",\n      \"journal\": \"Nature Microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model plus domain-specific binding assays plus ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"33986530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD4 demethylates RIG-I at constitutively methylated residues K18 and K146; demethylated RIG-I suppresses IL-6-STAT3 signaling; methylated RIG-I associates with AMPKα to inhibit HMGCR phosphorylation, promoting HMGCR enzymatic activity and cholesterol synthesis.\",\n      \"method\": \"Mass spectrometry identification of methylation sites; hepatocyte-specific RIG-I KO mice; specific antibodies against methylated lysine sites; RIG-I lysine mutant mice; functional signaling assays\",\n      \"journal\": \"Journal of Hematology & Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified PTM with KO mice and mutant mice, multiple functional readouts, single lab\",\n      \"pmids\": [\"36333807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Novel DDX58 variant R109C is a gain-of-function mutation causing lupus nephritis through reduced RIG-I autoinhibition, leading to RIG-I hyperactivation, increased K63 ubiquitination, and MAVS aggregation; JAK inhibitor therapy suppressed the elevated IFN signature.\",\n      \"method\": \"Whole-exome sequencing; biochemical IFN signaling assays; K63 ubiquitination assay; MAVS aggregation assay; single-cell RNA sequencing\",\n      \"journal\": \"JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function biochemical assays with multiple mechanistic readouts, single lab, novel variant\",\n      \"pmids\": [\"36261300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DUSP11 (RNA triphosphatase) removes 5'-triphosphates from both host and virus-derived RNAs, rendering them less active in inducing RIG-I-mediated immune responses; DUSP11 deficiency results in higher proportions of triphosphorylated viral transcripts, enhanced RIG-I activation, and attenuated virus replication rescued by RIG-I knockdown.\",\n      \"method\": \"DUSP11 knockdown/KO cells and mice; viral triphosphate RNA profiling; RIG-I activation assays; genetic rescue experiments\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular mechanism (triphosphate removal), in vivo mouse model, genetic rescue confirms RIG-I specificity\",\n      \"pmids\": [\"33184222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD97 negatively regulates RIG-I by upregulating RNF125 expression, which induces RNF125-mediated K48-linked ubiquitination of RIG-I at Lys181, leading to proteasomal degradation of RIG-I and suppression of IFN-I signaling.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination site mutagenesis; CD97-deficient mice; IFN-I signaling assays; VSV and SARS-CoV-2 replication assays\",\n      \"journal\": \"Cellular & Molecular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site mapping, Co-IP, in vivo KO model, single lab\",\n      \"pmids\": [\"37978243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RIG-I competes with SPOP to bind PD-L1, attenuating polyubiquitination and proteasomal degradation of PD-L1, thereby promoting PD-L1 stability and colon cancer immune evasion independently of type I interferon stimulation.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays; RIG-I knockdown/overexpression; in vivo tumor models\",\n      \"journal\": \"Journal for Immunotherapy of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing competition, ubiquitination assays, in vivo validation, single lab\",\n      \"pmids\": [\"37758653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATP and dsRNA binding triggers dimerization of RIG-I with conformational rearrangements exposing the tandem CARD domains; full-length RIG-I forms a 2:2 complex with dsRNA; phosphorylation-mimicking mutants S8E and T170E impair RIG-I binding to TRIM25, unanchored K63-linked polyubiquitin, and MAVS.\",\n      \"method\": \"Electron microscopy of RIG-I:dsRNA complex; co-immunoprecipitation; biochemical binding assays; phosphomimetic mutagenesis\",\n      \"journal\": \"Protein & Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EM structure plus mutagenesis and Co-IP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23264040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RIG-I recognizes metabolite-capped RNAs (NAD+, FAD, dephosphoCoA caps) as signaling ligands; these RNAs have high affinity for RIG-I, stimulate ATPase activity comparably to 5'ppp dsRNA, and activate innate antiviral signaling in cells.\",\n      \"method\": \"In vitro transcription with metabolite initiators; ATPase activity assays; binding assays; cellular IFN signaling assays\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution plus cellular assays, novel ligand class established, single lab\",\n      \"pmids\": [\"37326006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RIG-I bound to long dsRNA (>500 bp) with slow kinetics, forming stable complexes that did not dissociate; short dsRNA (<500 bp) formed complexes that dissociated efficiently in an ATP hydrolysis-dependent manner; dissociated RIG-I underwent homo-oligomerization acquiring ability to associate with MAVS, explaining length-dependent signaling.\",\n      \"method\": \"Binding kinetics assays; ATP hydrolysis assays; RIG-I oligomerization assays; MAVS association assays; biological activity in living cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinetic and biochemical assays, mechanistic model for length discrimination, single lab\",\n      \"pmids\": [\"37072508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMS-associated RIG-I mutations (E510V and Q517H) cause a loosened latch-gate engagement in apo RIG-I (in the HEL2i domain), dampening ATPase activity and impairing self-RNA (Cap2 moiety) proofreading, leading to increased immune activation.\",\n      \"method\": \"Hydrogen/deuterium exchange mass spectrometry (HDX-MS); single molecule magnetic tweezers (MT); ATPase assays; RNA proofreading assays\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple structural/biophysical methods (HDX-MS + single molecule MT) with functional validation, mechanistic explanation for SMS variants\",\n      \"pmids\": [\"35580046\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RIG-I (DDX58) is a cytoplasmic DExD/H-box RNA helicase that functions as an innate immune pattern recognition receptor by directly binding 5'-triphosphate blunt-ended dsRNA from RNA viruses; upon RNA binding, RIG-I undergoes ATP-dependent conformational changes and kinetic proofreading (ATP hydrolysis discriminates self from non-self RNA), releases its autoinhibited tandem CARD domains, which are activated by K63-linked polyubiquitination (by TRIM25 on CARDs and Riplet on CTD) and form a homo-tetrameric lock-washer structure that nucleates MAVS filament formation on mitochondria, triggering downstream IRF3 and NF-κB activation to induce type I interferons; this signaling is tightly regulated by multiple PTMs (K48-linked ubiquitination by RNF125/MARCH5 for degradation, SUMOylation, methylation, phosphorylation, ufmylation) and by deubiquitinases (CYLD, USP14, USP27X), and gain-of-function mutations in ATP-binding motifs cause constitutive activation leading to interferonopathies including atypical Singleton-Merten syndrome and lupus nephritis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RIG-I (DDX58) is a cytoplasmic RNA helicase that functions as a pattern-recognition receptor for the innate antiviral response, providing essential, non-redundant detection of distinct RNA virus classes including paramyxoviruses, influenza, flaviviruses, and Japanese encephalitis virus to drive IRF3-dependent type I interferon induction [#0, #2, #21]. Its activating ligand is RNA bearing a 5'-triphosphate end generated by viral polymerases, with physiological agonists corresponding to full-length 5'-triphosphate viral genomes rather than capped or modified RNA [#1, #4]. Structurally, RIG-I sheathes dsRNA across helicase domains HEL1/HEL2, the HEL2i insertion, and a C-terminal regulatory domain, with cryo-EM showing it can adopt either a signaling-conducive fold on viral 5'-triphosphate dsRNA or an autoinhibited fold on host RNA that triggers RNA release [#3, #13]. Self/non-self discrimination is enforced by an ATPase-powered kinetic-proofreading mechanism in which ATP hydrolysis dissociates self-RNAs faster than blunt-ended 5'-triphosphate dsRNA, conferring ~3000-fold selectivity gated by the autoinhibitory CARD2-HEL2i interface [#11, #14, #15]. Productive RNA engagement releases the tandem CARDs, which must homo-tetramerize into a lock-washer configuration—stabilized by TRIM25-mediated K63 polyubiquitination—to nucleate MAVS filament formation on mitochondria and propagate signaling [#6, #35]. Signaling output is tuned by an extensive PTM network: positive regulation through K63 ubiquitination (TRIM25, Riplet), SUMOylation, and ufmylation, and negative regulation through K48-linked degradative ubiquitination (RNF125, MARCH5), deubiquitination (CYLD, USP14, USP27X), and autophagic turnover [#7, #10, #17, #20, #25, #26, #27]. Gain-of-function mutations in the ATP-binding and latch-gate regions cause constitutive activation: C268F and E373A produce atypical Singleton-Merten syndrome, latch-gate variants impair proofreading, and R109C causes lupus nephritis via reduced autoinhibition [#5, #16, #31, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that RIG-I is a genuine, non-redundant antiviral sensor and defined its division of labor with MDA5 across virus classes, settling which receptor detects which pathogens.\",\n      \"evidence\": \"RIG-I and MDA5 knockout mice with viral challenge and interferon induction assays, plus cell-type-specific IRF3/IKK pathway placement\",\n      \"pmids\": [\"16625202\", \"16039576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular ligand recognized\", \"Did not resolve the structural basis of recognition\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the activating ligand as 5'-triphosphate RNA, defining the molecular signature that distinguishes viral from host RNA.\",\n      \"evidence\": \"Direct binding of 5'-triphosphate RNA to RIG-I with phosphatase-sensitivity controls and IFN-alpha assays\",\n      \"pmids\": [\"17038590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which authentic viral RNA species act as agonists during infection\", \"Did not address dsRNA end structure or length requirements\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the bona fide physiological agonists in infected cells as full-length 5'-triphosphate viral genomes, ruling out transcripts and cleaved self-RNA, and demonstrated a SUMOylation positive-regulation arm.\",\n      \"evidence\": \"Orthogonal RNA-IP, fractionation and genetic approaches in infected cells; SUMOylation and Co-IP assays\",\n      \"pmids\": [\"20144762\", \"21203974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how blunt-end and length selectivity are mechanistically achieved\", \"SUMOylation findings from a single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the domain architecture coupling RNA recognition to ATP hydrolysis, providing the structural framework for activation.\",\n      \"evidence\": \"X-ray crystallography of the RIG-I:dsRNA complex defining HEL1/HEL2/HEL2i, CTD and pincer\",\n      \"pmids\": [\"22000018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure did not capture the autoinhibited apo state or signaling conformation\", \"Did not show CARD oligomerization mechanism\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked ATP/dsRNA binding to conformational CARD exposure and dimerization, and showed phosphorylation as a brake on TRIM25/ubiquitin/MAVS engagement.\",\n      \"evidence\": \"Electron microscopy of RIG-I:dsRNA 2:2 complex with phosphomimetic mutagenesis and Co-IP\",\n      \"pmids\": [\"23264040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EM resolution limited; single lab\", \"Did not resolve the active CARD tetramer geometry\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the biochemical basis of self/non-self discrimination: ATPase-driven recycling from self-RNA, blunt-end selectivity, and the CARD2-HEL2i autoinhibitory gate; CARD tetramerization shown as prerequisite for MAVS nucleation.\",\n      \"evidence\": \"Quantitative ATPase/binding assays, chimeric duplexes, interface mutants, IFN-beta reporters; structural/biochemical reconstitution of CARD oligomerization\",\n      \"pmids\": [\"26612866\", \"25736886\", \"25942693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the full kinetic trajectory of proofreading\", \"CARD tetramer model partly from review synthesis\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that constitutive RIG-I activation causes human interferonopathy, establishing RIG-I gain-of-function as a disease mechanism.\",\n      \"evidence\": \"Exome sequencing of Singleton-Merten families with C268F/E373A; IFN activity and ISG assays plus structural context\",\n      \"pmids\": [\"25620203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not structurally resolve how the mutations mimic activation\", \"Limited to two families\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the kinetic-proofreading and translocation logic of RNA discrimination and the structural basis of ATP-independent gain-of-function activation.\",\n      \"evidence\": \"Transient-state kinetics and translocation assays with helicase mutants; crystal structure of the C268F:dsRNA complex\",\n      \"pmids\": [\"30270105\", \"30047865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how host RNA conformation differs structurally\", \"In vitro kinetics not directly mapped onto in-cell signaling timing\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the ligand repertoire to flaviviral genome 5' ends, established that short stem-loop RNAs activate without oligomerization, and detailed the PTM regulatory network.\",\n      \"evidence\": \"Affinity purification with NGS of DENV/ZIKV ligands; in vivo SLR delivery with RNA-seq; review of TRIM25/Riplet/RNF125/CYLD ubiquitin regulation\",\n      \"pmids\": [\"29996094\", \"29492454\", \"29354136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling oligomerization-independent short-RNA signaling with filament models\", \"Ubiquitin regulators summarized rather than newly reconstituted here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined multiple negative and positive regulators acting on RIG-I ubiquitination, antagonist RNA gating, and antagonist RNA conformational suppression.\",\n      \"evidence\": \"NLRP12-TRIM25 Co-IP with KO mice; USP14 deubiquitination; LRRC59/autophagy assays; biophysical 5'-monophosphate gating assays\",\n      \"pmids\": [\"30902577\", \"30466171\", \"31068071\", \"30784585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy and temporal order among regulators unresolved\", \"Several regulator findings from single labs\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established control of RIG-I activity at the level of ligand 5'-phosphate state and viral m6A modification as immune-escape strategies, plus additional DUB and ubiquitin regulators.\",\n      \"evidence\": \"DUSP11 triphosphatase KO with genetic rescue; recombinant m6A-mutant HMPV binding/conformation assays; USP27X DUB assays; MARCH5 K48 ubiquitination site mapping\",\n      \"pmids\": [\"33184222\", \"32015498\", \"32027733\", \"31881323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each escape route in natural infection unknown\", \"Several mechanisms validated in single labs\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered non-canonical and compartment-specific roles: nuclear RIG-I sensing, IFI16-mediated transcriptional and ubiquitin co-activation, an NHEJ-suppressive role at DNA breaks, and a second interferonopathy mutation.\",\n      \"evidence\": \"Subcellular fractionation/imaging of nuclear RIG-I; IFI16 KO mice with domain-specific binding and ChIP; XRCC4 Co-IP and NHEJ/repair assays; exome sequencing of R109C lupus nephritis\",\n      \"pmids\": [\"30097581\", \"33986530\", \"33846346\", \"36261300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear RIG-I import and signaling unclear\", \"DNA-break role mostly single-lab\", \"R109C variant from single family\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the conformational selectivity switch by cryo-EM, defined latch-gate proofreading defects in disease, established ufmylation as a positive arm, refined the resident-pool signaling model, and identified a lysine-methylation/metabolic axis.\",\n      \"evidence\": \"Cryo-EM of RIG-I with viral vs host RNA; HDX-MS and single-molecule tweezers on SMS latch-gate variants; UFL1/14-3-3-epsilon ufmylation assays; live-cell imaging of resident signaling pool; JMJD4 demethylation with KO mice\",\n      \"pmids\": [\"36272408\", \"35580046\", \"35394863\", \"36521492\", \"36333807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between resident-pool signaling and prior filament/oligomer models incompletely unified\", \"Metabolic and ufmylation arms from single labs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the ligand spectrum to metabolite-capped RNAs, defined length-dependent dissociation kinetics governing oligomerization, and revealed interferon-independent roles in PD-L1 stabilization and additional ubiquitin-mediated negative regulation.\",\n      \"evidence\": \"In vitro transcription with metabolite caps and ATPase/IFN assays; binding-kinetics/oligomerization assays on long vs short dsRNA; PD-L1/SPOP competition and tumor models; CD97-RNF125 K48 ubiquitination with KO mice\",\n      \"pmids\": [\"37326006\", \"37072508\", \"37758653\", \"37978243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological prevalence of metabolite-capped RNA ligands unknown\", \"Interferon-independent tumor role from single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse activation modes—oligomerization-independent short-RNA signaling, resident-pool signaling, and filament nucleation—are integrated into a single in-cell signaling pathway remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling short-RNA, resident-pool and filament data\", \"Temporal hierarchy of positive and negative PTM regulators undefined\", \"In-cell structure of the active CARD-MAVS interface not directly resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3, 13, 21, 36]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 11, 15, 16, 37]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [11, 15, 37]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1, 11, 13, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 22, 23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6, 9, 17, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 13, 35]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 16, 31, 38]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAVS\", \"TRIM25\", \"RNF125\", \"MARCH5\", \"USP14\", \"XRCC4\", \"ZYX\", \"NLRP12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}