Affinage

IFIH1

Interferon-induced helicase C domain-containing protein 1 · UniProt Q9BYX4

Length
1025 aa
Mass
116.7 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFIH1 (MDA5) is a cytoplasmic sensor of long double-stranded RNA that initiates type I and type III interferon responses, providing non-redundant antiviral immunity against picornaviruses and a range of other pathogens (PMID:16625202, PMID:17942531, PMID:34211037). Upon engaging long dsRNA, MDA5 assembles cooperative helical filaments along the RNA, a process that exposes its tandem N-terminal CARD domains to nucleate signaling through the mitochondrial adaptor MAVS and drive IRF3 activation (PMID:29395326, PMID:38985764, PMID:35168003). Filament-based activation is gated by an ATP-dependent RNA-proofreading function: adjacent subunits hydrolyze ATP cooperatively to disassemble filaments on shorter or imperfect duplexes while retaining longer bona fide viral dsRNA, conferring ligand selectivity (PMID:34795277, PMID:38309507). Productive signaling additionally requires TRIM65-catalyzed K63-linked ubiquitination of MDA5 at Lys743 for oligomerization, and is augmented by the co-activator PACT and by LGP2, which nucleates MDA5 filament assembly and promotes the active CARD-exposed conformation (PMID:28031478, PMID:28760879, PMID:33137199). MDA5 activity is restrained by ZFYVE1, which suppresses ligand binding and oligomerization, and by RNF144B, which directs K27/K33-linked ubiquitination and p62-dependent autophagic degradation (PMID:32251420, PMID:39285245). Tolerance to self is enforced by ADAR1-mediated A-to-I editing of endogenous dsRNAs, principally Alu-element and mRNA-derived stem-loops; loss of editing or gain-of-function MDA5 variants that recognize imperfect endogenous duplexes drive constitutive interferon production (PMID:26275108, PMID:29395326, PMID:37797622, PMID:41339703). Such variants cause type I interferonopathies including Aicardi-Goutières syndrome and Singleton-Merten syndrome, with mutations clustering near the ATP-binding region to increase RNA affinity or impair ATP-dependent disassembly (PMID:29395326, PMID:25620204, PMID:34795277, PMID:31898846). Diverse viral proteins antagonize this pathway by targeting MDA5 directly or its activating ubiquitination, and MDA5 also senses endogenous transposable-element transcripts to regulate hematopoietic stem cell quiescence (PMID:30814289, PMID:37956198, PMID:34253898).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2006 High

    Established MDA5 as a distinct, non-redundant innate sensor by showing it is specifically required to detect picornaviruses, separating its function from RIG-I.

    Evidence MDA5 knockout mice with in vivo viral challenge and type I IFN assays

    PMID:16625202

    Open questions at the time
    • Did not define the molecular ligand features distinguishing MDA5 from RIG-I substrates
    • Downstream adaptor not yet identified
  2. 2007 High

    Placed MDA5 in a defined signaling pathway by identifying MAVS/IPS-1 as the shared essential downstream adaptor and mapping virus-specific sensor usage.

    Evidence siRNA knockdown of RIG-I, MDA5, IPS-1 in fibroblasts with IRF3/ISG readouts

    PMID:17942531

    Open questions at the time
    • Mechanism of MDA5-MAVS coupling not resolved
    • Cell-type dependence of sensor requirements unclear
  3. 2007 Medium

    Showed that picornaviruses actively antagonize MDA5 through proteasome- and caspase-dependent degradation, framing the sensor as a target of viral immune evasion.

    Evidence Western blot with proteasome/caspase inhibitors and proteinase-mutant viruses in poliovirus-infected cells

    PMID:17267501

    Open questions at the time
    • Identity of the responsible E3 ligase/protease not determined
    • Single-lab mechanistic inference
  4. 2015 High

    Defined the self/nonself discrimination problem by showing ADAR1 editing of endogenous dsRNA prevents MDA5 from sensing self, with MDA5 deletion rescuing editing-deficient lethality.

    Evidence Adar1 E861A editing-deficient knock-in mice with MDA5 double-knockout rescue and genome-wide substrate mapping

    PMID:26275108

    Open questions at the time
    • Did not establish which specific endogenous RNAs trigger MDA5
    • PKR contribution not yet separated
  5. 2015 High

    Identified the activating post-translational switch by demonstrating TRIM65-mediated K63 ubiquitination at Lys743 is required for MDA5 oligomerization and antiviral function.

    Evidence Reciprocal Co-IP, site-specific ubiquitination mapping, Trim65-/- mice with EMCV challenge

    PMID:28031478

    Open questions at the time
    • How ubiquitination couples to filament/CARD assembly not structurally resolved
    • Regulation of TRIM65 recruitment unknown
  6. 2015 Medium

    Connected MDA5 gain-of-function directly to human disease, showing the p.Arg822Gln variant enhances IFN-beta induction and causes Singleton-Merten syndrome.

    Evidence Whole-exome sequencing, in vitro IFN-beta induction assays, patient interferon signature analysis

    PMID:25620204

    Open questions at the time
    • Structural basis of enhanced signaling not defined
    • Tissue specificity of pathology unexplained
  7. 2015 Medium

    Elucidated the activation mechanism of CARD signaling, showing MDA5 2CARD self-oligomerizes concentration-dependently without polyubiquitin, unlike RIG-I.

    Evidence Sedimentation velocity analytical ultracentrifugation of 2CARD with/without Ub4

    PMID:31697400

    Open questions at the time
    • Reconciliation with TRIM65 ubiquitin requirement in cells not addressed
    • Single-lab biophysical study
  8. 2018 High

    Identified the endogenous immunogenic ligand class by showing Alu retroelement dsRNAs activate MDA5 in AGS and that disease variants form filaments on imperfect duplexes wild-type MDA5 cannot.

    Evidence RNase-protection/RNA-seq ligand identification, AGS variant functional analysis, filament assembly assays

    PMID:29395326

    Open questions at the time
    • Quantitative threshold of duplex imperfection tolerated not defined
    • Relationship to ATPase proofreading not yet structurally linked
  9. 2018 Medium

    Extended the viral antagonism map by showing EMCV 2C binds MDA5 to suppress IFN-beta, validated by reverse genetics with a single residue determinant.

    Evidence Co-IP, V26 site-directed mutagenesis, rescued-virus reverse genetics, IFN-beta assays

    PMID:30312637

    Open questions at the time
    • Step in MDA5 activation blocked by 2C not pinpointed
    • Single-lab study
  10. 2019 Medium

    Identified the CARD domain as a viral target by showing picornaviral 3Dpol polymerases bind MDA5 CARDs to inhibit IFN-beta induction.

    Evidence Co-IP, pulldown, IFN-beta promoter reporter assays for EV71 and CVB3

    PMID:30814289

    Open questions at the time
    • Whether 3Dpol blocks oligomerization or MAVS coupling unclear
    • No in vivo validation
  11. 2020 Medium

    Defined LGP2 as a positive regulator acting as a filament nucleator that drives MDA5 into an active CARD-exposed conformation.

    Evidence Biochemical filament assembly, limited proteolysis, ATP hydrolysis assays

    PMID:33137199

    Open questions at the time
    • In vivo significance of nucleation not established
    • Single-lab biochemical study
  12. 2020 High

    Identified ZFYVE1 as a sensor-specific negative regulator restraining MDA5 ligand binding and oligomerization in vivo.

    Evidence Reciprocal Co-IP, Zfyve1-/- mice with EMCV and VSV challenge, oligomerization/ligand-binding assays

    PMID:32251420

    Open questions at the time
    • Structural basis of ZFYVE1-MDA5 inhibition not resolved
    • Regulation of ZFYVE1 itself unknown
  13. 2020 Medium

    Established a unifying mutational mechanism for interferonopathies by showing IFIH1 GOF variants cluster near the ATP-binding region and either raise RNA affinity or slow ATP hydrolysis/filament disassembly.

    Evidence Cohort genetics with in vitro ATP hydrolysis and RNA-binding assays on 27 variants

    PMID:31898846

    Open questions at the time
    • Did not provide structural mechanism for individual variants
    • Genotype-phenotype severity correlation incomplete
  14. 2021 High

    Provided the structural mechanism of ATP-dependent proofreading, showing the M854K variant disrupts the ATPase cycle allosterically to stabilize binding on Alu:Alu dsRNA and constitutively signal.

    Evidence Cryo-EM of MDA5-dsRNA filaments, ATPase and dsRNA-binding assays, IFN reporter assays

    PMID:34795277

    Open questions at the time
    • Generality of the allosteric mechanism across all GOF variants not tested
    • Dynamics of filament turnover in cells not captured
  15. 2021 Medium

    Extended MDA5's antiviral role to SARS-CoV-2, establishing it as the sensor driving type I/III IFN via MAVS-IRF3 in lung epithelium.

    Evidence siRNA knockdown of MDA5/MAVS/IRF3 in infected Calu-3 cells with IFN/cytokine assays

    PMID:34211037

    Open questions at the time
    • Identity of activating SARS-CoV-2 RNA species not defined here
    • Knockdown rather than knockout system
  16. 2021 High

    Revealed a physiological role beyond infection, showing MDA5 senses chemotherapy-induced transposable-element transcripts to drive HSC exit from quiescence.

    Evidence Mda5-/- mice, chemotherapy challenge, TE transcript manipulation, HSC quiescence/repopulation assays

    PMID:34253898

    Open questions at the time
    • Mechanism linking TE sensing to quiescence exit incompletely defined
    • Whether other stresses engage the same axis unknown
  17. 2022 High

    Demonstrated in vivo causality of an MDA5 GOF variant for organ-specific autoimmunity, with phenotype strictly dependent on MAVS and IFNAR.

    Evidence Whole-body and cardiomyocyte-specific hMDA5 R779H transgenic mice with MAVS-/- and IFNAR-/- crosses

    PMID:35168003

    Open questions at the time
    • Endogenous RNA ligand driving the in vivo phenotype not identified
    • Basis of tissue-specific susceptibility unclear
  18. 2022 Medium

    Expanded viral evasion strategies, showing flavivirus prM proteins disrupt MDA5-MAVS complex formation and that SARS-CoV-2 Nsp16 methylation shields viral RNA from MDA5.

    Evidence Co-IP and IRF3 localization assays (prM); recombinant Nsp16-mutant virus in MDA5-KO cells

    PMID:36285486 PMID:36639652

    Open questions at the time
    • Structural detail of complex disruption not resolved
    • Single-lab studies
  19. 2023 High

    Separated the ADAR1 effector pathways, showing loss of editing specifically activates MDA5 whereas loss of cytoplasmic ADAR1p150 dsRNA-binding activates PKR.

    Evidence Adar1p150-/- mice with MDA5/PKR double-knockout epistasis and survival analysis

    PMID:37797622

    Open questions at the time
    • Whether MDA5 and PKR sense overlapping or distinct RNA pools unresolved
    • Crosstalk between the two effectors not defined
  20. 2023 Medium

    Identified a SARS-CoV-2 evasion mechanism converging on MDA5 ubiquitination, showing Nsp8 sequesters TRIM4 to block K63-ubiquitination of MDA5.

    Evidence Co-IP, ubiquitination assays, IFN reporter assays in SARS-CoV-2 infection

    PMID:37956198

    Open questions at the time
    • Relationship between TRIM4 and TRIM65 ubiquitination of MDA5 not reconciled
    • Single-lab study
  21. 2024 High

    Resolved the cooperative biochemistry of filament turnover and LGP2's mechanistic role, showing adjacent subunits hydrolyze ATP cooperatively to disassemble filaments while LGP2 nucleates shorter filaments noncooperatively.

    Evidence Electron microscopy, ATPase and nucleotide-specificity assays, filament assembly, molecular modeling

    PMID:38309507

    Open questions at the time
    • How cooperative disassembly tunes ligand selectivity quantitatively not defined
    • In-cell relevance of LGP2-shortened filaments untested
  22. 2024 High

    Identified MDA5 as the dedicated sensor of HIV-1 intron-containing RNA, requiring filament formation, dephosphorylation and MAVS association, with RIG-I dispensable.

    Evidence shRNA screen, nontargetable rescue, dominant-negative mutants, V-protein inhibitor, f-CLIP RNA-IP in primary dendritic cells

    PMID:38985764

    Open questions at the time
    • Structural features of HIV-1 RNA recognized by MDA5 not defined
    • Role in HIV pathogenesis in vivo unknown
  23. 2024 High

    Defined the MDA5 degradation arm of negative regulation, showing RNF144B drives K27/K33-ubiquitination of MDA5 CARDs at Lys23/43 for p62-mediated autophagic destruction.

    Evidence Co-IP, ubiquitination mapping, Rnf144b-/- mice with EMCV challenge, p62 autophagy assays

    PMID:39285245

    Open questions at the time
    • Trigger that activates RNF144B toward MDA5 unknown
    • Interplay with activating TRIM65 ubiquitination not resolved
  24. 2025 Medium

    Characterized the endogenous immunogenic dsRNA repertoire, showing it is a small mRNA-enriched, intron-depleted subset whose immunogenicity is dampened by ADAR1 editing.

    Evidence Transcriptomic identification with MDA5-dependent immunogenicity validation and ADAR1 editing correlation

    PMID:41339703

    Open questions at the time
    • Structural determinants making these RNAs immunogenic not fully defined
    • Single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How activating (TRIM65 K63) and degradative (RNF144B K27/K33) ubiquitination, LGP2/PACT co-activation, and ATP-dependent proofreading are integrated in real time to set the threshold distinguishing self from viral dsRNA remains unresolved.
  • No unified model coupling ubiquitin state to filament dynamics
  • Spatiotemporal regulation of activating vs degradative modifications unknown
  • Mechanism setting per-cell activation threshold undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0060089 molecular transducer activity 3 GO:0140657 ATP-dependent activity 3 GO:0140098 catalytic activity, acting on RNA 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4
Partners
ADAR1LGP2MAVSPACTRNF144BTRIM4TRIM65ZFYVE1
Complex memberships
MDA5-MAVS signaling complexMDA5-dsRNA filament

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 MDA5 (IFIH1) recognizes long poly(I:C) dsRNA and is specifically required for innate immune detection of picornaviruses, while RIG-I detects in vitro-transcribed short dsRNAs and other RNA viruses; MDA5-/- mice are highly susceptible to picornavirus infection, establishing distinct and non-redundant roles for each helicase. MDA5 knockout mice, in vivo viral challenge, type I IFN production assays Nature High 16625202
2007 IPS-1/MAVS is an essential downstream adaptor for both RIG-I and MDA5 antiviral signaling; MDA5 is individually dispensable for innate immune signaling triggered by reovirus and dengue virus in cultured fibroblasts, but RIG-I is essential for influenza A, influenza B, and RSV. siRNA knockdown of RIG-I, MDA5, and IPS-1 in cultured fibroblasts; IRF3 activation and ISG expression assays Journal of virology High 17942531
2007 MDA5 protein is degraded in poliovirus-infected cells via a proteasome- and caspase-dependent mechanism (not by viral proteinases 2Apro or 3Cpro), correlating with apoptosis induction; this degradation is proposed as a viral strategy to antagonize type I IFN production. Western blot, proteasome inhibitors, caspase inhibitors, proteinase-mutant viruses, puromycin-induced apoptosis controls Journal of virology Medium 17267501
2015 ADAR1-mediated A-to-I editing of endogenous dsRNA stem-loop structures in 3' UTRs of cellular transcripts is required to prevent MDA5 from sensing endogenous dsRNA as nonself; concurrent deletion of MDA5 rescues the embryonic lethality of editing-deficient Adar1(E861A/E861A) mice. Editing-deficient knock-in mice (Adar1 E861A), MDA5 double-knockout rescue, genome-wide RNA editing substrate identification Science High 26275108
2015 TRIM65 specifically interacts with MDA5 and catalyzes K63-linked ubiquitination of MDA5 at lysine 743, which is required for MDA5 oligomerization and activation; Trim65-/- mice cannot produce type I IFN and are more susceptible to EMCV infection. Co-immunoprecipitation, ubiquitination assays, Trim65-/- knockout mice, EMCV challenge, IRF3 activation assays The Journal of experimental medicine High 28031478
2018 Constitutive activation of MDA5 in Aicardi-Goutières syndrome results from loss of tolerance to Alu retroelement-derived dsRNAs; AGS-associated MDA5 variants display reduced sensitivity to duplex structural irregularities and can form signaling-competent filaments on imperfect Alu-dsRNAs, whereas wild-type MDA5 cannot efficiently recognize them. RNase-protection/RNA-seq approach to identify endogenous MDA5 ligands; functional analysis of AGS variants; MDA5 filament assembly assays on Alu-dsRNAs Cell High 29395326
2015 An IFIH1 gain-of-function missense mutation (p.Arg822Gln) causes Singleton-Merten syndrome by enhancing MDA5 function in IFN-β induction; in vitro functional analysis confirmed enhanced MDA5-mediated interferon signaling; interferon signature genes were upregulated in SMS patient blood and dental cells. Whole-exome sequencing, in vitro IFN-β induction assays with mutant IFIH1, immunohistochemistry, interferon signature gene expression American journal of human genetics Medium 25620204
2017 PACT (dsRNA-binding protein) functions as an essential coactivator of MDA5 by promoting dsRNA-induced oligomerization of MDA5; PACT-knockout cells show severely impaired virus- and poly(I:C)-induced MDA5-dependent type I IFN responses; PACT had no influence on MDA5-mediated NF-κB activation and required dsRNA interaction for its action. PACT knockout and knockdown cells, overexpression, oligomerization assays, IRF3-dependent IFN assays, colocalization studies Journal of immunology Medium 28760879
2020 LGP2 facilitates MDA5 filament assembly by acting as a nucleator; LGP2 is incorporated into MDA5-dsRNA filaments (average inter-molecular distance ~32 nm), induces conformational changes in MDA5 promoting CARD domain exposure, and promotes conversion of MDA5 to an active conformation capable of downstream signaling even after filament dissociation by ATP hydrolysis. Biochemical filament assembly assays, biophysical approaches, limited protease digestion, ATP hydrolysis assays Nucleic acids research Medium 33137199
2021 The disease-associated MDA5 variant M854K lacks ATPase activity, binds more stably to Alu:Alu dsRNA, and constitutively activates interferon signaling in the absence of exogenous RNA; cryo-EM structures of MDA5-dsRNA filaments reveal that K854 forms polar bonds constraining subdomain conformation and disrupting key steps in the ATPase cycle (RNA footprint expansion and helical twist modulation), inhibiting ATP-dependent RNA proofreading via an allosteric mechanism. CryoEM structural determination, ATPase activity assays, dsRNA binding assays, interferon signaling reporter assays Nature communications High 34795277
2024 Adjacent MDA5 subunits in MDA5-dsRNA filaments hydrolyze ATP cooperatively, inducing cooperative filament disassembly; consecutive rounds of ATP hydrolysis amplify the filament footprint; LGP2 binds dsRNA at internal sites via noncooperative ATP hydrolysis, has low nucleic acid selectivity (can hydrolyze GTP and CTP as well as ATP), promotes MDA5 filament nucleation yielding shorter filaments, and makes key contacts with MDA5 via its C-terminal tail. Electron microscopy, biochemical ATPase assays, nucleotide specificity assays, filament assembly assays, molecular modeling The Journal of biological chemistry High 38309507
2019 Enterovirus 71 RNA-dependent RNA polymerase (3Dpol) interacts specifically with the CARD domains of MDA5 and inhibits MDA5-mediated IFN-β promoter activation; coxsackievirus B3 3Dpol also interacts with MDA5 and downregulates MDA5-initiated antiviral signaling. Co-immunoprecipitation, reporter assays for IFN-β promoter activation, pulldown assays Journal of virology Medium 30814289
2018 EMCV non-structural protein 2C interacts with MDA5 to inhibit IFN-β signaling; mutation of amino acid V26 of 2C abolishes both IFN-β inhibition and MDA5 interaction; rescued viruses with 2C mutations induce significantly higher IFN-β levels. Co-immunoprecipitation, site-directed mutagenesis, reverse genetics (rescued virus), IFN-β reporter and mRNA assays Antiviral research Medium 30312637
2019 MDA5 2CARD self-associates into large oligomers in a concentration-dependent manner in the absence of polyubiquitin, whereas RIG-I 2CARD requires unanchored K63-linked polyubiquitin for tetramerization; polyubiquitin (Ub4) binds MDA5 2CARD only weakly (1:1 and 2:1 stoichiometries) and does not induce 2CARD oligomerization, indicating distinct assembly mechanisms for RIG-I and MDA5 signaling. Sedimentation velocity analytical ultracentrifugation, multi-signal sedimentation velocity analysis Protein science Medium 31697400
2021 MDA5 is required for type I and type III IFN induction in lung epithelial cells (Calu-3) upon SARS-CoV-2 infection; this IFN induction further requires MAVS and IRF3; induction of IL-6 and TNF by SARS-CoV-2 is independent of the MDA5-MAVS-IRF3 axis. siRNA knockdown of MDA5, MAVS, IRF3; IFN and cytokine production assays in SARS-CoV-2-infected Calu-3 cells Scientific reports Medium 34211037
2022 SARS-CoV-2 2'-O-methyltransferase Nsp16 shields viral RNA from MDA5-mediated recognition; recombinant SARS-CoV-2 with catalytically inactive Nsp16 (Nsp16mut) is highly immunogenic with strongly enhanced type I IFN release, and this elevated immunogenicity is absent in MDA5-deficient cells. Recombinant virus with Nsp16 catalytic mutant, MDA5 knockout cells, IFN production assays EMBO reports Medium 36285486
2023 SARS-CoV-2 nonstructural protein Nsp8 binds to both MDA5 and TRIM4, impairing TRIM4-mediated K63-linked polyubiquitination of MDA5, thereby suppressing MDA5 activation and downstream IRF3/NF-κB signaling and IFN production. Co-immunoprecipitation, ubiquitination assays, IFN reporter assays, SARS-CoV-2 infection studies PLoS pathogens Medium 37956198
2020 ZFYVE1 specifically interacts with MDA5 (not RIG-I), binds viral RNA, and decreases MDA5 ligand binding and oligomerization, functioning as a specific negative regulator of MDA5-mediated (but not RIG-I-mediated) innate antiviral responses; Zfyve1-/- mice are protected from EMCV (MDA5-sensed) but not VSV (RIG-I-sensed) lethality. Co-immunoprecipitation, Zfyve1-/- knockout mice, viral challenge (EMCV and VSV), MDA5 oligomerization and ligand-binding assays PLoS pathogens High 32251420
2024 IFIH1 (MDA5) is the innate immune receptor required for detection of intron-containing RNA from the HIV-1 provirus in primary human dendritic cells; MDA5 filament formation, dephosphorylation, and association with MAVS are all required for innate immune activation; MDA5 specifically enriches unspliced HIV-1 RNA over two orders of magnitude as shown by formaldehyde cross-linking immunoprecipitation (f-CLIP); DDX58/RIG-I knockdown had no effect. shRNA loss-of-function screen, nontargetable IFIH1 rescue, Nipah virus V protein inhibitor, dominant-negative IFIH1 mutants, f-CLIP RNA immunoprecipitation, RNA-Seq Proceedings of the National Academy of Sciences of the United States of America High 38985764
2023 Loss of ADAR1p150 activates both MDA5 and PKR; deleting both MDA5 and PKR completely rescues the embryonic lethality of Adar1p150-/- mice to adulthood, whereas removing MDA5 or PKR alone provides only limited or no rescue; loss of ADAR1-mediated RNA editing specifically activates MDA5, whereas loss of cytoplasmic ADAR1p150 or its dsRNA-binding activity enables PKR activation. Adar1p150-/- knockout mice, MDA5/PKR double-knockout epistasis, rescue experiments, survival analysis Molecular cell High 37797622
2021 Transposable element transcripts (ERV and LINE superfamily copies) generated during chemotherapy-induced chromatin reorganization bind to and activate MDA5 in haematopoietic stem cells (HSCs), generating an inflammatory response required for HSC exit from quiescence; Mda5-/- HSCs retain quiescence and show better long-term repopulation after chemotherapy. Mda5-/- knockout mice, chemotherapy challenge, chromatin reorganization analysis, TE transcript overexpression/knockdown, HSC quiescence and repopulation assays Nature cell biology High 34253898
2024 RNF144B specifically interacts with MDA5 CARDs and promotes K27/K33-linked polyubiquitination of MDA5 at lysine 23 and 43, which promotes autophagic degradation of MDA5 via p62; Rnf144b-/- mice show greatly enhanced IFN production and significantly higher survival upon EMCV infection. Co-immunoprecipitation, ubiquitination mapping, Rnf144b-/- knockout mice, EMCV challenge, p62-mediated autophagy assays EMBO reports High 39285245
2022 Flavivirus prM protein from TBEV interacts with both MDA5 and MAVS, interfering with MDA5-MAVS complex formation and thereby impeding IRF3 nuclear translocation/dimerization and inhibiting RLR antiviral signaling; ZIKV and WNV prM similarly interact with both MDA5 and MAVS. Co-immunoprecipitation, IRF3 localization assays, IFN-I reporter assays, viral replication assays Cell & bioscience Medium 36639652
2022 Transgenic mice expressing human MDA5 R779H mutant spontaneously develop myocarditis and nephritis with upregulated type I IFNs; cardiomyocyte-specific expression of hMDA5 R779H causes cardiomegaly and inflammatory cytokine upregulation; the phenotype requires intact MDA5-MAVS signaling and IFNAR (R779H Tg Mavs-/- and R779H Tg Ifnar-/- mice show no phenotype). Transgenic mice (whole-body and cardiomyocyte-specific), MAVS-/- and IFNAR-/- double knockouts, bone marrow transplantation, histopathology Journal of autoimmunity High 35168003
2021 IFIH1 promotes IRF3 nuclear translocation in macrophages via a MyD88-dependent mechanism when stimulated by LPS, in addition to its known RNA-sensing role; IFIH1 knockdown abolishes LPS-induced IRF3 activation and M1 polarization in RAW264.7 and BMDM cells. shRNA knockdown, IFIH1 overexpression lentiviral constructs, macrophage polarization assays, IRF3 activation measurements, GSEA Frontiers in immunology Low 33519803
2025 Immunogenic dsRNAs that activate MDA5 constitute a small fraction of all cellular dsRNAs, are highly enriched in mRNAs and depleted of introns (consistent with cytosolic localization), and their MDA5-dependent immunogenicity is dampened by ADAR1-mediated RNA editing. Transcriptomic/RNA-seq identification of immunogenic dsRNAs, MDA5-dependent immunogenicity validation, ADAR1 editing correlation analysis Nature genetics Medium 41339703
2011 Overexpression of Ifih1 (MDA5) in transgenic mice leads to a chronic type I IFN state with viral resistance; spontaneous MDA5 activation alone is not sufficient to initiate autoimmune or inflammatory pathology, but accelerates autoantibody production, glomerulonephritis, and early lethality on an FcγR2B-deficient lupus-susceptible background. Ifih1 multi-copy transgenic mice, viral challenge, autoimmune phenotyping, FcγR2B-deficient cross Journal of immunology Medium 22205024
2020 IFIH1 gain-of-function mutations cluster near the ATP-binding region of MDA5 and are associated with either increased RNA-binding affinity or decreased ATP hydrolysis efficiency and filament disassembly rate, establishing a common mutational mechanism for type I interferonopathies. Cohort genetic analysis with in vitro functional characterization of 27 mutations; ATP hydrolysis and RNA-binding assays Human mutation Medium 31898846

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
2007 Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. Journal of virology 845 17942531
2015 RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science (New York, N.Y.) 771 26275108
2015 Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American journal of medical genetics. Part A 507 25604658
2008 MDA5/RIG-I and virus recognition. Current opinion in immunology 451 18272355
2018 Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation. Cell 346 29395326
2014 Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5. Frontiers in immunology 314 25101084
2009 The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody. Rheumatology (Oxford, England) 267 20015976
2018 A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation. Trends in microbiology 253 30201512
2021 Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies. Frontiers in immunology 210 34745149
2020 Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases. Neurology 196 32487712
2015 A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. American journal of human genetics 182 25620204
2021 Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis. Clinical reviews in allergy & immunology 162 33405101
2009 Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity. Pharmacology & therapeutics 162 19615405
2017 Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: A concise review with an emphasis on distinctive clinical features. Journal of the American Academy of Dermatology 157 29229575
2016 TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity. The Journal of experimental medicine 154 28031478
2007 MDA-5 is cleaved in poliovirus-infected cells. Journal of virology 153 17267501
2023 Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress. Nature reviews. Rheumatology 115 38057474
2021 The RNA sensor MDA5 detects SARS-CoV-2 infection. Scientific reports 111 34211037
2015 LGP2 synergy with MDA5 in RLR-mediated RNA recognition and antiviral signaling. Cytokine 102 25794939
2014 MDA5 and LGP2: accomplices and antagonists of antiviral signal transduction. Journal of virology 100 24850739
2020 Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Human mutation 95 31898846
2022 Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications. Nature communications 89 36309526
2023 ADAR1p150 prevents MDA5 and PKR activation via distinct mechanisms to avert fatal autoinflammation. Molecular cell 83 37797622
2010 Reduced expression of IFIH1 is protective for type 1 diabetes. PloS one 81 20844740
2021 Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry. Rheumatology international 80 33774723
2022 Management of MDA-5 antibody positive clinically amyopathic dermatomyositis associated interstitial lung disease: A systematic review. Seminars in arthritis and rheumatism 77 35134633
2011 Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 73 22205024
2020 Viral RNA recognition by LGP2 and MDA5, and activation of signaling through step-by-step conformational changes. Nucleic acids research 72 33137199
2013 Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Autoimmunity 71 23734776
2015 Reduced expression of the MDA5 Gene IFIH1 prevents autoimmune diabetes. Diabetes 70 25591872
2007 Pregnancy and interferon tau regulate RSAD2 and IFIH1 expression in the ovine uterus. Reproduction (Cambridge, England) 67 17244754
2021 Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration. Nature cell biology 66 34253898
2015 The RIG-I-like helicase receptor MDA5 (IFIH1) is involved in the host defense against Candida infections. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 63 25579795
2015 MDA5-filament, dynamics and disease. Current opinion in virology 63 25676875
2022 IFIH1/IRF1/STAT1 promotes sepsis associated inflammatory lung injury via activating macrophage M1 polarization. International immunopharmacology 61 36462334
2022 Anti-MDA5 dermatomyositis after COVID-19 vaccination: a case-based review. Rheumatology international 46 35661906
2018 Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome. Trends in pharmacological sciences 44 30606502
2017 PACT Facilitates RNA-Induced Activation of MDA5 by Promoting MDA5 Oligomerization. Journal of immunology (Baltimore, Md. : 1950) 44 28760879
2022 Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction. EMBO reports 43 36285486
2015 Effects of type 1 diabetes-associated IFIH1 polymorphisms on MDA5 function and expression. Current diabetes reports 43 26385483
2018 Anti-MDA5 Antibody Spectrum in Western World. Current rheumatology reports 41 30382445
2021 Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis responds to rituximab therapy. Clinical rheumatology 39 33411136
2021 To "Z" or not to "Z": Z-RNA, self-recognition, and the MDA5 helicase. PLoS genetics 38 33983939
2020 Pangolins Lack IFIH1/MDA5, a Cytoplasmic RNA Sensor That Initiates Innate Immune Defense Upon Coronavirus Infection. Frontiers in immunology 38 32574256
2021 Pharmacologic Treatment of Anti-MDA5 Rapidly Progressive Interstitial Lung Disease. Current treatment options in rheumatology 36 34603940
2017 Interplay between dengue virus and Toll-like receptors, RIG-I/MDA5 and microRNAs: Implications for pathogenesis. Antiviral research 36 28965915
2017 Recurrent and Prolonged Infections in a Child with a Homozygous IFIH1 Nonsense Mutation. Frontiers in genetics 36 29018476
2010 Interferon induced with helicase C domain 1 (IFIH1) and virus-induced autoimmunity: a review. Viral immunology 36 20121398
2022 Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner. The Journal of experimental medicine 35 36346347
2018 Encephalomyocarditis virus 2C protein antagonizes interferon-β signaling pathway through interaction with MDA5. Antiviral research 35 30312637
2024 MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C). EBioMedicine 33 38723554
2021 IFIH1 Contributes to M1 Macrophage Polarization in ARDS. Frontiers in immunology 33 33519803
2019 Role of Enteroviral RNA-Dependent RNA Polymerase in Regulation of MDA5-Mediated Beta Interferon Activation. Journal of virology 32 30814289
2017 MDA5 autoantibody-another indicator of clinical diversity in dermatomyositis. Annals of translational medicine 32 28480196
2023 SARS-CoV-2 Nsp8 suppresses MDA5 antiviral immune responses by impairing TRIM4-mediated K63-linked polyubiquitination. PLoS pathogens 27 37956198
2013 Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility. Genes and immunity 27 23535865
2020 Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development. Microorganisms 25 32635205
2020 ADAR1 Regulates Early T Cell Development via MDA5-Dependent and -Independent Pathways. Journal of immunology (Baltimore, Md. : 1950) 23 32169840
2019 Pattern Recognition by Melanoma Differentiation-Associated Gene 5 (Mda5) in Teleost Fish: A Review. Frontiers in immunology 23 31080451
2023 MDA5 RNA-sensing pathway activation by Mycobacterium tuberculosis promotes innate immune subversion and pathogen survival. JCI insight 22 37725440
2013 Targeting TLR3 with no RIG-I/MDA5 activation is effective in immunotherapy for cancer. Expert opinion on therapeutic targets 22 23414438
2024 PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity. Virologica Sinica 21 38272236
2015 Are RIG-1 and MDA5 Expressions Associated with Chronic HBV Infection? Viral immunology 21 26485346
2024 IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus. Proceedings of the National Academy of Sciences of the United States of America 20 38985764
2023 Flavivirus prM interacts with MDA5 and MAVS to inhibit RLR antiviral signaling. Cell & bioscience 20 36639652
2020 ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response. PLoS pathogens 20 32251420
2025 CD19 CAR-T cell therapy in a pediatric patient with MDA5+ dermatomyositis and rapidly progressive interstitial lung disease. Med (New York, N.Y.) 19 40306284
2023 Changes in anti-MDA5 antibody titres and serum cytokine levels before and after diagnosis of anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford, England) 19 36326436
2022 Anti-MDA5 Amyopathic Dermatomyositis-A Diagnostic and Therapeutic Challenge. Life (Basel, Switzerland) 18 35892910
2021 MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA. Nature communications 18 34795277
2020 Transcriptomic Analysis of the Chicken MDA5 Response Genes. Genes 18 32183248
2021 Foot-and-Mouth Disease Virus Evades Innate Immune Response by 3C-Targeting of MDA5. Cells 17 33572945
2019 Oligomerization of RIG-I and MDA5 2CARD domains. Protein science : a publication of the Protein Society 17 31697400
2018 Comprehensive assessment of the association between genes on JAK-STAT pathway (IFIH1, TYK2, IL-10) and systemic lupus erythematosus: a meta-analysis. Archives of dermatological research 17 30171347
2023 MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance. JCI insight 15 36512407
2022 Intracellular virus sensor MDA5 mutation develops autoimmune myocarditis and nephritis. Journal of autoimmunity 15 35168003
2022 MDA5 expression is associated with TGF-β-induced fibrosis: potential mechanism of interstitial lung disease in anti-MDA5 dermatomyositis. Rheumatology (Oxford, England) 15 35412608
2022 Bat Employs a Conserved MDA5 Gene to Trigger Antiviral Innate Immune Responses. Frontiers in immunology 15 35677039
2021 Mitochondrial morphology and MAVS-IFN1 signaling pathway in muscles of anti-MDA5 dermatomyositis. Annals of clinical and translational neurology 15 33576578
2021 Distribution of anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses in MDA5+ dermatomyositis. Rheumatology (Oxford, England) 15 33742662
2017 Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. PloS one 15 28234905
2016 MDA-5 activation by cytoplasmic double-stranded RNA impairs endothelial function and aggravates atherosclerosis. Journal of cellular and molecular medicine 15 27130701
2015 MDA5 complements TLR3 in suppression of neuroblastoma. Oncotarget 15 26208481
2015 Functions of MDA5 and its domains in response to GCRV or bacterial PAMPs. Fish & shellfish immunology 15 26260315
2023 Anti-MDA5-positive dermatomyositis and remission in a single referral centre population. Clinical and experimental rheumatology 14 36826791
2013 The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus. Arquivos brasileiros de endocrinologia e metabologia 13 24402011
2023 Chicken miR-26a-5p modulates MDA5 during highly pathogenic avian influenza virus infection. Developmental and comparative immunology 12 37611883
2021 ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway. Life science alliance 12 34969816
2025 DNMT inhibition epigenetically restores the cGAS-STING pathway and activates RIG-I/MDA5-MAVS to enhance antitumor immunity. Acta pharmacologica Sinica 11 40830678
2025 ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity. Nature genetics 11 41339703
2024 Contrasting functions of ATP hydrolysis by MDA5 and LGP2 in viral RNA sensing. The Journal of biological chemistry 11 38309507
2023 MDA5 Enhances Invasive Candida albicans Infection by Regulating Macrophage Apoptosis and Phagocytosis/Killing Functions. Inflammation 11 37740789
2022 Double-Stranded RNA Induces Mortality in an MDA5-Mediated Type I Interferonopathy Model. Journal of immunology (Baltimore, Md. : 1950) 11 36426976
2022 Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19. Immunogenetics 11 36434151
2022 Interaction between chicken TRIM25 and MDA5 and their role in mediated antiviral activity against IBDV infection. Frontiers in microbiology 11 36519174
2021 KAP1-Mediated Epigenetic Suppression in Anti-RNA Viral Responses by Direct Targeting RIG-I and MDA5. Journal of immunology (Baltimore, Md. : 1950) 11 34497149
2020 Role of CARD Region of MDA5 Gene in Canine Influenza Virus Infection. Viruses 11 32178353
2024 RNF144B negatively regulates antiviral immunity by targeting MDA5 for autophagic degradation. EMBO reports 10 39285245
2021 Repeated MDA5 Gene Loss in Birds: An Evolutionary Perspective. Viruses 10 34834938

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