Affinage

RIGI

Antiviral innate immune response receptor RIG-I · UniProt O95786

Length
925 aa
Mass
106.6 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    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

    PMID:16039576 PMID:16625202

    Open questions at the time
    • Did not identify the molecular ligand recognized
    • Did not resolve the structural basis of recognition
  2. 2006 High

    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

    PMID:17038590

    Open questions at the time
    • Did not establish which authentic viral RNA species act as agonists during infection
    • Did not address dsRNA end structure or length requirements
  3. 2010 High

    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

    PMID:20144762 PMID:21203974

    Open questions at the time
    • Did not explain how blunt-end and length selectivity are mechanistically achieved
    • SUMOylation findings from a single lab
  4. 2011 High

    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

    PMID:22000018

    Open questions at the time
    • Static structure did not capture the autoinhibited apo state or signaling conformation
    • Did not show CARD oligomerization mechanism
  5. 2012 Medium

    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

    PMID:23264040

    Open questions at the time
    • EM resolution limited; single lab
    • Did not resolve the active CARD tetramer geometry
  6. 2015 High

    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

    PMID:25736886 PMID:25942693 PMID:26612866

    Open questions at the time
    • Did not capture the full kinetic trajectory of proofreading
    • CARD tetramer model partly from review synthesis
  7. 2015 High

    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

    PMID:25620203

    Open questions at the time
    • Did not structurally resolve how the mutations mimic activation
    • Limited to two families
  8. 2018 High

    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

    PMID:30047865 PMID:30270105

    Open questions at the time
    • Did not address how host RNA conformation differs structurally
    • In vitro kinetics not directly mapped onto in-cell signaling timing
  9. 2018 High

    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

    PMID:29354136 PMID:29492454 PMID:29996094

    Open questions at the time
    • Reconciling oligomerization-independent short-RNA signaling with filament models
    • Ubiquitin regulators summarized rather than newly reconstituted here
  10. 2019 High

    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

    PMID:30466171 PMID:30784585 PMID:30902577 PMID:31068071

    Open questions at the time
    • Hierarchy and temporal order among regulators unresolved
    • Several regulator findings from single labs
  11. 2020 High

    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

    PMID:31881323 PMID:32015498 PMID:32027733 PMID:33184222

    Open questions at the time
    • Quantitative contribution of each escape route in natural infection unknown
    • Several mechanisms validated in single labs
  12. 2021 Medium

    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

    PMID:30097581 PMID:33846346 PMID:33986530 PMID:36261300

    Open questions at the time
    • Mechanism of nuclear RIG-I import and signaling unclear
    • DNA-break role mostly single-lab
    • R109C variant from single family
  13. 2022 High

    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

    PMID:35394863 PMID:35580046 PMID:36272408 PMID:36333807 PMID:36521492

    Open questions at the time
    • Relationship between resident-pool signaling and prior filament/oligomer models incompletely unified
    • Metabolic and ufmylation arms from single labs
  14. 2023 Medium

    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

    PMID:37072508 PMID:37326006 PMID:37758653 PMID:37978243

    Open questions at the time
    • Physiological prevalence of metabolite-capped RNA ligands unknown
    • Interferon-independent tumor role from single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140657 ATP-dependent activity 5 GO:0140299 molecular sensor activity 4 GO:0060089 molecular transducer activity 3 GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-73894 DNA Repair 1
Partners
MARCH5MAVSNLRP12RNF125TRIM25USP14XRCC4ZYX

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Gene-targeted RIG-I knockout and MDA5 knockout mice; interferon induction assays; viral challenge experiments Nature High 16625202
2006 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. Direct binding assay (5'-triphosphate RNA to RIG-I); phosphatase sensitivity assay; genomic RNA from negative-strand RNA viruses; interferon-alpha response assays Science High 17038590
2005 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. Gene-targeted RIG-I knockout mice; IFN induction assays; cell-type-specific analysis Immunity High 16039576
2011 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. X-ray crystallography of RIG-I:dsRNA complex Cell High 22000018
2010 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. Three orthogonal approaches (RNA immunoprecipitation, biochemical fractionation, genetic approaches) to identify RIG-I agonists in infected cells Cell High 20144762
2015 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. Exome sequencing; functional assays measuring IFN activity and ISG expression; structural analysis of mutant positions; cytopathic assays in human trabecular meshwork cells American Journal of Human Genetics High 25620203
2015 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. Structural analysis; biochemical reconstitution of CARD oligomerization; MAVS filament formation assays Current Opinion in Virology Medium 25942693
2018 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. Ubiquitination assays; knockout/knockdown studies; domain-specific ubiquitination mapping Frontiers in Immunology High 29354136
2019 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. Co-immunoprecipitation; ubiquitination assays; myeloid-cell-specific Nlrp12 knockout mice; VSV infection assays Cell Host & Microbe High 30902577
2017 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. Bimolecular fluorescence complementation (BiFC); super-resolution microscopy; subcellular localization studies in virus-infected cells Journal of Virology Medium 27807226
2010 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. SUMOylation assay; co-immunoprecipitation; IFN-I production assays Protein & Cell Medium 21203974
2018 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. Transient-state kinetics; ATPase activity assays; translocation assays; helicase motif mutagenesis Molecular Cell High 30270105
2019 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. Quantitative biophysical binding assays; immunological signaling assays; conformational analysis Cell Reports High 30784585
2022 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. High-resolution cryo-EM structural determination; functional validation Molecular Cell High 36272408
2015 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. Quantitative binding and ATPase assays; CARD deletion and CARD2-HEL2i interface point mutants; selectivity measurements Nucleic Acids Research High 26612866
2015 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. In vitro ATPase assays; RNA binding assays; chimeric ribo/deoxyribonucleotide duplexes; IFN-β reporter assays mBio High 25736886
2018 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. Crystal structure of RIG-I C268F:dsRNA complex; functional signaling assays; ATP-independence experiments eLife High 30047865
2022 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. Protein interaction assays (co-IP); UFM1 conjugation assays; genetic loss-of-function of ufmylation pathway; IFN induction assays PNAS Medium 35394863
2021 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. Co-immunoprecipitation; DSB recruitment assays; NHEJ repair assays; RIG-I KO and overexpression; in vivo influenza virus infection in XRCC4-silenced mice Nature Communications Medium 33846346
2018 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). In vivo RNA delivery to mice; RNA sequencing for genome-wide expression; comparison with poly(I:C) which activates multiple sensors Science Advances High 29492454
2019 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. In vivo ubiquitination assay; co-immunoprecipitation; site-directed mutagenesis; MARCH5 RING domain deletion Cellular Signalling Medium 31881323
2018 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. Affinity purification of RIG-I:RNA complexes; next-generation sequencing; in vitro RNA production and stimulation assays Cell Reports High 29996094
2018 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. Live-cell imaging; subcellular fractionation; nuclear RIG-I identification; IAV and SeV infection assays; HBV pregenomic RNA sensing Nature Communications Medium 30097581
2022 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. Live-cell imaging of RIG-I following dsRNA stimulation; kinetic analysis of signaling complex formation Molecular Cell Medium 36521492
2020 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. Recombinant HMPV with m6A site mutations; RNA pulldown/binding assays; conformational assays; RIG-I KO cell lines; in vivo cotton rat infection Nature Microbiology High 32015498
2019 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. Co-immunoprecipitation; in vitro deubiquitination assay; siRNA knockdown; USP14-specific inhibitor (IU1) in vitro and in vivo European Journal of Immunology Medium 30466171
2020 USP27X removes K63-linked polyubiquitin chains from RIG-I in a deubiquitinase-dependent manner to negatively regulate RIG-I-mediated antiviral signaling. siRNA library screening; co-immunoprecipitation; deubiquitination assays; overexpression and knockdown of USP27X PLoS Pathogens Medium 32027733
2019 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. Co-immunoprecipitation; autophagy flux assays; KO cells; IFN signaling measurements Autophagy Medium 31068071
2017 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. Yeast two-hybrid screening; co-immunoprecipitation; proximity ligation assay; ZYX knockdown with IFN-β reporter; influenza A virus RNA stimulation Scientific Reports Medium 28928438
2021 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. IFI16 KO cells and p204-deficient mice; domain-specific binding assays; K63 ubiquitination assay; RNA Pol II ChIP; IFN-I production assays Nature Microbiology High 33986530
2022 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. 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 of Hematology & Oncology Medium 36333807
2021 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. Whole-exome sequencing; biochemical IFN signaling assays; K63 ubiquitination assay; MAVS aggregation assay; single-cell RNA sequencing JASN Medium 36261300
2020 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. DUSP11 knockdown/KO cells and mice; viral triphosphate RNA profiling; RIG-I activation assays; genetic rescue experiments Genes & Development High 33184222
2023 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. Co-immunoprecipitation; ubiquitination site mutagenesis; CD97-deficient mice; IFN-I signaling assays; VSV and SARS-CoV-2 replication assays Cellular & Molecular Immunology Medium 37978243
2023 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. Co-immunoprecipitation; ubiquitination assays; RIG-I knockdown/overexpression; in vivo tumor models Journal for Immunotherapy of Cancer Medium 37758653
2012 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. Electron microscopy of RIG-I:dsRNA complex; co-immunoprecipitation; biochemical binding assays; phosphomimetic mutagenesis Protein & Cell Medium 23264040
2023 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. In vitro transcription with metabolite initiators; ATPase activity assays; binding assays; cellular IFN signaling assays Nucleic Acids Research Medium 37326006
2023 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. Binding kinetics assays; ATP hydrolysis assays; RIG-I oligomerization assays; MAVS association assays; biological activity in living cells Scientific Reports Medium 37072508
2022 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. Hydrogen/deuterium exchange mass spectrometry (HDX-MS); single molecule magnetic tweezers (MT); ATPase assays; RNA proofreading assays Nucleic Acids Research High 35580046

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 3071 16625202
2006 5'-Triphosphate RNA is the ligand for RIG-I. Science (New York, N.Y.) 1957 17038590
2005 Cell type-specific involvement of RIG-I in antiviral response. Immunity 1068 16039576
2007 Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. Journal of virology 845 17942531
2010 RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell 497 20144762
2015 RIG-I in RNA virus recognition. Virology 357 25749629
2018 RIG-I and Other RNA Sensors in Antiviral Immunity. Annual review of immunology 355 29677479
2011 Structural insights into RNA recognition by RIG-I. Cell 350 22000018
2014 Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5. Frontiers in immunology 314 25101084
2017 Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways. Trends in immunology 286 28073693
2020 N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I. Nature microbiology 216 32015498
2021 The molecular mechanism of RIG-I activation and signaling. Immunological reviews 202 34514601
2015 How RIG-I like receptors activate MAVS. Current opinion in virology 194 25942693
2013 Master sensors of pathogenic RNA - RIG-I like receptors. Immunobiology 184 23896194
2015 Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. American journal of human genetics 176 25620203
2021 SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation. The EMBO journal 173 34101213
2011 RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity. Current opinion in virology 168 21949557
2018 Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers. Cancer research 140 30224377
2012 A structure-based model of RIG-I activation. RNA (New York, N.Y.) 121 23118418
2007 RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity. Cytokine & growth factor reviews 118 17683970
2017 Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway. Journal of innate immunity 114 28877527
2012 MicroRNAs in the regulation of TLR and RIG-I pathways. Cellular & molecular immunology 107 23262976
2021 IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection. Nature microbiology 106 33986530
2019 RIG-I activation is critical for responsiveness to checkpoint blockade. Science immunology 102 31519811
2014 Mitophagy enhances oncolytic measles virus replication by mitigating DDX58/RIG-I-like receptor signaling. Journal of virology 100 24574393
2018 RIG-I Recognizes the 5' Region of Dengue and Zika Virus Genomes. Cell reports 97 29996094
2018 A minimal RNA ligand for potent RIG-I activation in living mice. Science advances 93 29492454
2018 Regulation of RIG-I Activation by K63-Linked Polyubiquitination. Frontiers in immunology 92 29354136
2014 Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis. The Journal of pathology 87 24604766
2014 Sensing viral invasion by RIG-I like receptors. Current opinion in microbiology 85 24968321
2018 Nuclear-resident RIG-I senses viral replication inducing antiviral immunity. Nature communications 84 30097581
2019 NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25. Cell host & microbe 82 30902577
2017 Subcellular Localizations of RIG-I, TRIM25, and MAVS Complexes. Journal of virology 79 27807226
2017 RIG-I: a multifunctional protein beyond a pattern recognition receptor. Protein & cell 79 28593618
2010 The chase for the RIG-I ligand--recent advances. Molecular therapy : the journal of the American Society of Gene Therapy 78 20461060
2020 The Caenorhabditis elegans RIG-I Homolog DRH-1 Mediates the Intracellular Pathogen Response upon Viral Infection. Journal of virology 73 31619561
2022 Robust delivery of RIG-I agonists using extracellular vesicles for anti-cancer immunotherapy. Journal of extracellular vesicles 70 35430766
2019 LRRC59 modulates type I interferon signaling by restraining the SQSTM1/p62-mediated autophagic degradation of pattern recognition receptor DDX58/RIG-I. Autophagy 70 31068071
2018 Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment. Oncotarget 70 29989043
2017 RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease. EMBO molecular medicine 64 28377495
2011 Ubiquitin-mediated modulation of the cytoplasmic viral RNA sensor RIG-I. Journal of biochemistry 64 21890623
2018 RIG-I Uses an ATPase-Powered Translocation-Throttling Mechanism for Kinetic Proofreading of RNAs and Oligomerization. Molecular cell 63 30270105
2015 Both RIG-I and MDA5 detect alphavirus replication in concentration-dependent mode. Virology 63 26550947
2019 LGP2 binds to PACT to regulate RIG-I- and MDA5-mediated antiviral responses. Science signaling 61 31575732
2011 RIG-I like receptors in antiviral immunity and therapeutic applications. Viruses 61 21994761
2011 Differential recognition of viral RNA by RIG-I. Virulence 58 21422808
2010 SUMOylation of RIG-I positively regulates the type I interferon signaling. Protein & cell 58 21203974
2009 Approaching the RNA ligand for RIG-I? Immunological reviews 58 19120476
2019 RIG-I Selectively Discriminates against 5'-Monophosphate RNA. Cell reports 51 30784585
2022 Signaling from the RNA sensor RIG-I is regulated by ufmylation. Proceedings of the National Academy of Sciences of the United States of America 50 35394863
2021 Differential roles of RIG-I like receptors in SARS-CoV-2 infection. Military Medical Research 50 34488908
2017 RNA virus receptor Rig-I monitors gut microbiota and inhibits colitis-associated colorectal cancer. Journal of experimental & clinical cancer research : CR 49 28057020
2021 Lipotoxicity reduces DDX58/Rig-1 expression and activity leading to impaired autophagy and cell death. Autophagy 48 33966599
2021 Reciprocal regulation of RIG-I and XRCC4 connects DNA repair with RIG-I immune signaling. Nature communications 47 33846346
2020 Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy. The Journal of clinical investigation 47 32427578
2007 RIG-I: tri-ing to discriminate between self and non-self RNA. Trends in immunology 47 17307033
2018 Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome. Trends in pharmacological sciences 44 30606502
2015 RIG-I ATPase activity and discrimination of self-RNA versus non-self-RNA. mBio 44 25736886
2020 The Innate Immune Signalling Pathways: Turning RIG-I Sensor Activation Against Cancer. Cancers 43 33121210
2016 Standing on three legs: antiviral activities of RIG-I against influenza viruses. Current opinion in immunology 43 27318973
2023 Senecavirus A-induced glycolysis facilitates virus replication by promoting lactate production that attenuates the interaction between MAVS and RIG-I. PLoS pathogens 42 37126525
2022 The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands. Molecular cell 41 36272408
2021 OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis. Science immunology 41 34272227
2014 Activation and regulation of pathogen sensor RIG-I. Cytokine & growth factor reviews 41 25212896
2013 Parts, assembly and operation of the RIG-I family of motors. Current opinion in structural biology 40 24878341
2018 USP14 promotes K63-linked RIG-I deubiquitination and suppresses antiviral immune responses. European journal of immunology 39 30466171
2008 RIG-I and dsRNA-induced IFNbeta activation. PloS one 39 19115016
2022 JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis. Journal of hematology & oncology 37 36333807
2022 Mutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling. Nature communications 37 36402769
2022 A rapid RIG-I signaling relay mediates efficient antiviral response. Molecular cell 36 36521492
2019 Dual targeting of RIG-I and MAVS by MARCH5 mitochondria ubiquitin ligase in innate immunity. Cellular signalling 36 31881323
2020 Apigenin suppresses influenza A virus-induced RIG-I activation and viral replication. Journal of medical virology 35 32776519
2018 Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants. eLife 35 30047865
2017 RIG-I expression in perifascicular myofibers is a reliable biomarker of dermatomyositis. Arthritis research & therapy 35 28738907
2022 Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation. Journal of the American Society of Nephrology : JASN 34 36261300
2017 RIG-I Activation Protects and Rescues from Lethal Influenza Virus Infection and Bacterial Superinfection. Molecular therapy : the journal of the American Society of Gene Therapy 32 28760668
2015 The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection. Nucleic acids research 32 26612866
2017 RIG-I Resists Hypoxia-Induced Immunosuppression and Dedifferentiation. Cancer immunology research 29 28468914
2020 RIG-I aggravates interstitial fibrosis via c-Myc-mediated fibroblast activation in UUO mice. Journal of molecular medicine (Berlin, Germany) 28 32036390
2020 DUSP11-mediated control of 5'-triphosphate RNA regulates RIG-I sensitivity. Genes & development 28 33184222
2021 DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation. Journal of medical genetics 27 33495304
2017 Zyxin stabilizes RIG-I and MAVS interactions and promotes type I interferon response. Scientific reports 26 28928438
2017 RIG-I and IL-6 are negative-feedback regulators of STING induced by double-stranded DNA. PloS one 25 28806404
2023 CD97 negatively regulates the innate immune response against RNA viruses by promoting RNF125-mediated RIG-I degradation. Cellular & molecular immunology 24 37978243
2022 Ultraviolet light induces HERV expression to activate RIG-I signalling pathway in keratinocytes. Experimental dermatology 24 35332586
2019 The RIG-I pathway is involved in peripheral T cell lymphopenia in patients with dermatomyositis. Arthritis research & therapy 24 31142372
2023 RIG-I promotes immune evasion of colon cancer by modulating PD-L1 ubiquitination. Journal for immunotherapy of cancer 23 37758653
2020 USP27X negatively regulates antiviral signaling by deubiquitinating RIG-I. PLoS pathogens 23 32027733
2019 Targeting intrinsic RIG-I signaling turns melanoma cells into type I interferon-releasing cellular antitumor vaccines. Oncoimmunology 23 30906666
2016 Novel interferonopathies associated with mutations in RIG-I like receptors. Cytokine & growth factor reviews 23 26993858
2016 What Really Rigs Up RIG-I? Journal of innate immunity 23 27438016
2022 A loosened gating mechanism of RIG-I leads to autoimmune disorders. Nucleic acids research 22 35580046
2020 Small-Molecule Antagonists of the RIG-I Innate Immune Receptor. ACS chemical biology 22 31944652
2020 RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness. The Journal of allergy and clinical immunology 22 32035159
2012 Structural and biochemical studies of RIG-I antiviral signaling. Protein & cell 22 23264040
2023 Mechanisms of length-dependent recognition of viral double-stranded RNA by RIG-I. Scientific reports 20 37072508
2023 RIG-I recognizes metabolite-capped RNAs as signaling ligands. Nucleic acids research 20 37326006
2019 Cytoplasm and Beyond: Dynamic Innate Immune Sensing of Influenza A Virus by RIG-I. Journal of virology 20 30760567
2016 RIG-I inhibits the MAPK-dependent proliferation of BRAF mutant melanoma cells via MKP-1. Cellular signalling 20 26829212
2015 The catcher in the RIG-I. Cytokine 19 26168692

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