{"gene":"IFIT3","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2011,"finding":"IFIT3 bridges MAVS and TBK1 on mitochondria to potentiate antiviral signaling: the TPR motif (E164/E165) of IFIT3 interacts with the N-terminus (K38) of TBK1, physically linking TBK1 to the MAVS complex and promoting TBK1 activation and IRF3 phosphorylation. Disruption of this interaction attenuates TBK1 and IRF3 activation.","method":"Co-immunoprecipitation, ectopic expression, siRNA knockdown, mutagenesis (E164/E165 and K38), IRF3 phosphorylation assays, antiviral replication assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with defined interaction residues confirmed by mutagenesis, functional epistasis via KD/OE with defined signaling readouts, replicated in multiple cell systems","pmids":["21813773"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of cap 0 RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3 reveals that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending IFIT1 half-life (increasing steady-state protein levels) and (2) allosterically reshaping the IFIT1 RNA-binding channel to enhance specificity for cap 0 but not cap 1 or 5'-ppp RNA. Mouse Ifit3 lacks this C-terminal domain and does not bind mouse Ifit1.","method":"X-ray crystallography, biochemical binding assays, mutagenesis, cell-based half-life/stability assays, viral restriction assays with 2'-O methylation-deficient viruses","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, mutagenesis, multiple orthogonal biochemical methods in a single rigorous study","pmids":["29525521"],"is_preprint":false},{"year":2018,"finding":"IFIT1 and IFIT3 interact via a conserved YxxxL motif in the C-terminus of each protein. IFIT2 and IFIT3 homodimers dissociate to form a more stable heterodimer that also associates with IFIT1. IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to cap0 Zika virus reporter mRNA, and enhances IFIT1-mediated translation inhibition.","method":"In vitro reconstitution of IFIT complexes, electrophoretic mobility shift assays (EMSA), mutagenesis (YxxxL motif), translation inhibition assays, protein stability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, multiple orthogonal functional assays; independently corroborates PMID:29525521","pmids":["29554348"],"is_preprint":false},{"year":2006,"finding":"RIG-G (IFIT3) induces G1/S cell cycle arrest by interacting with JAB1 (CSN5), sequestering it and preventing JAB1-dependent, ubiquitin/proteasome-mediated degradation of p27, thereby elevating p27 levels. Additionally, RIG-G causes c-Myc downregulation, leading to p21 upregulation, contributing to growth arrest.","method":"Ectopic expression in U937 cells, Co-immunoprecipitation (RIG-G/JAB1 interaction), cell cycle analysis (flow cytometry), Western blot for p21/p27/c-Myc, ubiquitin/proteasome inhibition experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for binding partner, mechanistic dissection of p27 degradation pathway with multiple readouts in a single rigorous study","pmids":["17050680"],"is_preprint":false},{"year":2013,"finding":"RIG-G (IFIT3) disrupts the integrity and stability of the COP9 signalosome (CSN) complex, dramatically reducing cellular CSN content and inhibiting its regulatory roles in assembly and activation of cullin-RING ubiquitin E3 ligases (CRL). This causes excessive CRL activation (via CSN-mediated deneddylation inhibition), decreasing Cul1 and βTrCP levels, and impairing CSN-associated deubiquitination (USP15 recruitment), resulting in accumulation of IκBα.","method":"Co-immunoprecipitation, Western blot for CSN subunits/Cul1/βTrCP/IκBα, deneddylation assays, ubiquitination assays, ectopic expression of RIG-G","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays in a single lab, ectopic expression approach without full mutagenesis validation","pmids":["23415865"],"is_preprint":false},{"year":2017,"finding":"IFIT3 binds STAT1 and STAT2 to enhance STAT1-STAT2 heterodimerization and nuclear translocation upon IFN-α treatment, thereby promoting IFN-α effector signaling. This was demonstrated by co-immunoprecipitation in HCC cells and confirmed functionally in vitro and in vivo.","method":"Co-immunoprecipitation (IFIT3/STAT1 and IFIT3/STAT2), nuclear fractionation, ectopic expression and knockdown, in vitro and in vivo antitumor assays","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional epistasis (KD/OE), single lab, mechanistic follow-up included","pmids":["28295457"],"is_preprint":false},{"year":2018,"finding":"IFIT3 interacts with both STING and TBK1, and promotes IFNβ expression downstream of the cGAS/STING pathway. Knockdown of IFIT3 reduced VACV70-induced IFNβ expression, while overexpression produced an opposite effect.","method":"Co-immunoprecipitation (IFIT3/STING and IFIT3/TBK1), gain- and loss-of-function experiments, IFNβ expression assays in human monocytes","journal":"Arthritis & rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating two binding partners, functional KD/OE with defined readout, single lab","pmids":["29806091"],"is_preprint":false},{"year":2020,"finding":"IFIT3 directly interacts with the mitochondrial channel protein VDAC2, and stabilizes the interaction of VDAC2 with O-GlcNAc transferase (OGT), promoting O-GlcNAcylation of VDAC2. This increased VDAC2 O-GlcNAcylation protects PDAC cells from chemotherapy-induced apoptosis, conferring drug resistance.","method":"Co-immunoprecipitation, mass spectrometry, subcellular fractionation, confocal immunofluorescence, knockdown/overexpression, apoptosis assays, chromatin-immunoprecipitation","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and MS identified interaction, post-translational modification mechanism characterized, multiple functional assays; single lab","pmids":["32641986"],"is_preprint":false},{"year":2019,"finding":"IFIT1 and IFIT3 interact with ANXA2 (Annexin A2) by co-immunoprecipitation and LC-MS/MS, and this interaction enhances endosomal recycling of phosphorylated EGFR (p-EGFRY1068). Depletion of ANXA2 abolished p-EGFR and p-AKT expression in IFIT1- or IFIT3-overexpressing OSCC cells.","method":"Co-immunoprecipitation, LC-MS/MS, siRNA knockdown of ANXA2, Western blot for p-EGFR/p-AKT, xenograft and orthotopic mouse models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS for binding partner identification, epistasis via ANXA2 knockdown with defined signaling readout, single lab","pmids":["30626937"],"is_preprint":false},{"year":2023,"finding":"UBE2O ubiquitinates IFIT3 at lysine 236 (K236), targeting it for proteasomal degradation and reducing IFN-α signaling efficacy in hepatocellular carcinoma. Knockdown of UBE2O increased IFIT3 expression and enhanced IFN-α antitumor effects; rescue experiments with K236 mutant IFIT3 confirmed dependence on this ubiquitination site.","method":"Proteomic analysis, mass spectrometry, co-immunoprecipitation, mutagenesis (K236A), knockdown/overexpression, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site identified by MS with mutagenesis rescue validation, multiple functional assays, single lab","pmids":["38129382"],"is_preprint":false},{"year":2024,"finding":"PDCoV nsp5 (main protease) cleaves porcine IFIT3 at Gln-406, antagonizing type I interferon signaling. A pIFIT3-Q406A mutant was resistant to nsp5-mediated cleavage and exhibited greater ability to inhibit PDCoV infection than wild-type IFIT3. Similar cleavage of endogenous IFIT3 by nsp5 proteins of multiple human coronaviruses (but not alphacoronaviruses) was observed.","method":"Transcriptomic analysis, site-directed mutagenesis (Q406A), in vitro cleavage assays, ectopic expression, viral replication assays, Western blot","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro cleavage assay with mutagenesis validation at defined cleavage site, multiple viral contexts tested, functional consequence demonstrated","pmids":["38289117"],"is_preprint":false},{"year":2025,"finding":"The IFIT2-IFIT3 heterodimer, formed through a domain-swapped structure resolved by cryo-EM at 3.2 Å, recognizes viral mRNA 5' ends with short untranslated regions (<50 nucleotides) as a molecular pattern, inhibiting their translation. This complex mediates antiviral activity against viruses with short 5' UTRs (e.g., VSV, parainfluenza virus 3).","method":"Cryo-EM structure determination (3.2 Å), in vitro translation inhibition assays, mutagenesis, viral replication assays","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation, in vitro translation assays, multiple viral systems tested","pmids":["41093992"],"is_preprint":false},{"year":2025,"finding":"IFIT3 directly binds RNA via a conserved surface composed of residues shared with IFIT2 paralogs, located near the dimerization interface. Mutation of this RNA-binding surface reduced IFIT3's ability to promote IAV gene expression and translation efficiency without affecting IFIT2/IFIT3 dimerization, establishing that RNA binding is functionally separable from dimerization and required for pro-viral activity during IAV infection.","method":"Electrophoretic mobility shift assay (EMSA), RNA-binding site identification (RBS-ID), mutagenesis, co-immunoprecipitation, IAV replication/translation assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct RNA binding validated by EMSA, binding site identified and mutated with functional consequence for translation and replication, dimerization separability demonstrated by Co-IP","pmids":["40497724"],"is_preprint":false},{"year":2023,"finding":"IFIT3 mediates TBK1 phosphorylation as an upstream regulatory factor, activating plasmacytoid dendritic cells (pDCs) and contributing to SSc pathogenesis. IFIT3-knockout mice showed reduced skin and lung fibrosis in the SSc model.","method":"Single-cell RNA sequencing, in vitro cell experiments, CRISPR/Cas9 IFIT3-knockout mouse model, TBK1 phosphorylation assays, cytokine measurements","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with in vitro mechanistic follow-up (TBK1 phosphorylation), single lab","pmids":["39305055"],"is_preprint":false},{"year":2022,"finding":"IFIT3 promotes the anti-HBV effect of IFN-α in a STAT2-dependent manner: knockdown of IFIT3 inhibited STAT2 phosphorylation while overexpression promoted it, and IFIT3 overexpression enhanced IFN-α-triggered ISG expression (MxA, OAS1, PKR). This effect was abrogated by JAK inhibitor ruxolitinib.","method":"shRNA knockdown, overexpression, Western blot for pSTAT2, qRT-PCR for ISGs, HBV antigen/DNA quantification, ruxolitinib epistasis experiment","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined signaling readout and epistasis via pharmacological JAK inhibition, single lab","pmids":["36314949"],"is_preprint":false},{"year":2016,"finding":"HSV-1 tegument protein UL41, a viral endoribonuclease, counteracts IFIT3 antiviral activity by degrading IFIT3 mRNA, reducing its accumulation. UL41-null mutant HSV-1 replication was restricted by ectopic IFIT3, and stable IFIT3 knockdown facilitated UL41-null virus replication.","method":"Ectopic expression of UL41, UL41-null mutant virus (R2621), stable IFIT3 knockdown, mRNA quantification, viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis using null mutant virus with complementary KD/OE experiments, mechanism at mRNA level demonstrated, single lab","pmids":["27681138"],"is_preprint":false},{"year":2023,"finding":"IFIT1 and IFIT3 form a complex with BAX and N-GSDME, directing N-GSDME translocation to mitochondria and increasing mitochondrial membrane permeabilization, thereby triggering pyroptosis in myeloma and leukemia cells.","method":"Co-immunoprecipitation, RNA sequencing, siRNA knockdown, caspase/GSDME activation assays, mitochondrial fractionation, venetoclax combination experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying multi-protein complex, subcellular fractionation showing mitochondrial translocation, KD with functional readout; single lab","pmids":["38462032"],"is_preprint":false},{"year":2019,"finding":"HBV regulatory protein HBx activates NF-κB, which in turn directly drives IFIT3 transcription, and overexpressed IFIT3 paradoxically enhances HBV replication in HepG2 cells.","method":"Transfection with pHBV1.3 plasmid, NF-κB activation assays, IFIT3 overexpression, HBV replication assays","journal":"Frontiers in microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic link between NF-κB and IFIT3 transcription implied but not confirmed by direct promoter binding assay in this abstract; functional consequence demonstrated","pmids":["31681236"],"is_preprint":false},{"year":2018,"finding":"IFIT3 (ISG60) constitutes a negative feedback loop downstream of TLR3/IFN-β signaling in brain capillary endothelial cells: knockdown of IFIT3 increased poly IC-induced IFN-β and CXCL10 expression, demonstrating that IFIT3 limits these responses.","method":"siRNA knockdown of ISG60, poly IC treatment, ELISA/qRT-PCR for IFN-β and CXCL10","journal":"Journal of neuroimmunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single KD experiment with defined readout, single lab, no binding partner or molecular mechanism identified","pmids":["30195920"],"is_preprint":false},{"year":2015,"finding":"IFIT3 shows binding to JNK and STAT1 in pancreatic cancer cells (COLO357FG), and STAT1 is an important inducer of IFIT3 expression. Transgenic IFIT3 expression increased VEGF and IL-6 secretion, chemoresistance, and decreased starvation-induced apoptosis.","method":"Co-immunoprecipitation (IFIT3/JNK and IFIT3/STAT1), ectopic expression, in vitro/in vivo tumor assays, cytokine quantification","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying binding partners, functional follow-up present but mechanism not fully resolved, single lab","pmids":["25650658"],"is_preprint":false},{"year":2010,"finding":"STAT1 significantly enhances the IRF-9/STAT2 complex or IRF-1 on RIG-G (IFIT3) induction through the activated JAK-STAT pathway; however, STAT1 is not essential for RIG-G expression. In STAT1-deficient cells, IRF-1 can induce RIG-G expression via ISREs, but cannot upregulate IRF-9 and STAT2 unless STAT1 is reconstituted. RIG-G expression is independent of the classical JAK-STAT pathway but greatly amplified by it.","method":"STAT1-deficient U3A cell reconstitution, luciferase reporter assays, Western blot, IRF-1/IRF-9/STAT2 overexpression","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis using isogenic STAT1-deficient cell reconstitution system, multiple transcription factor perturbations with defined readout; single lab","pmids":["21056555"],"is_preprint":false},{"year":2025,"finding":"IFIT3 preferentially associates with N6-methyladenosine (m6A)-modified HCV genomic RNA and host transcripts to restrict HCV infection. Two structural regions are required for RNA binding: TPR1-2 (required for IFIT2 interaction but dispensable for HCV RNA binding) and a predicted helical hairpin between TPR6 and TPR7 (required for HCV RNA binding but dispensable for IFIT2 interaction). Loss of either region diminished antiviral activity.","method":"HyperTRIBE-seq (transcriptome-wide RNA-binding site mapping), co-purification with m6A-modified RNA probes, m6A inhibition experiments, mutagenesis of TPR domains and helical hairpin, HCV replication assays","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (HyperTRIBE, biochemical binding, mutagenesis, functional assays) in a single preprint; not yet peer-reviewed","pmids":["41929069"],"is_preprint":true},{"year":2025,"finding":"When IFIT1 is expressed at high levels without IFIT3, it can inhibit translation of certain self ISG mRNAs (including ISG15 and IFITM1). IFIT1:IFIT3 complex formation rescues these self-ISGs from IFIT1-mediated translation inhibition. IFIT3 directly binds IFIT1 and protects it from proteasomal degradation, ensuring IFIT1 accumulation only occurs alongside IFIT3—a mechanism to prevent self-targeting while enabling antiviral activity.","method":"Ectopic expression of IFIT1 with/without IFIT3, siRNA knockdown, proteasome inhibitor experiments, translation assays, viral replication assays (Semliki Forest virus)","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and proteasomal degradation mechanism with multiple functional readouts; preprint not yet peer-reviewed, but mechanistically detailed","pmids":["bio_10.1101_2025.11.17.688928"],"is_preprint":true},{"year":2026,"finding":"IFIT3 acts as a molecular bridge between STING and the deubiquitinase USP18, inhibiting ubiquitination-mediated degradation of STING and amplifying downstream cGAS-STING inflammatory signaling. IFIT3 promoted M1 macrophage polarization and early lung injury; IFIT3 knockdown ameliorated early lung injury in vivo.","method":"Co-immunoprecipitation (IFIT3/STING/USP18), ubiquitination assays, IFIT3 knockdown in vivo (AAV-mediated), flow cytometry for M1/M2 polarization, cytokine assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defining ternary complex with functional epistasis via in vivo KD; single lab, mechanism partially inferred","pmids":["41686220"],"is_preprint":false},{"year":2025,"finding":"IFIT3 interacts with DVL2 (dishevelled 2) in the cytoplasm of lung squamous cell carcinoma cells and promotes phosphorylation of DVL2 at threonine 224, increasing phosphorylation of GSK-3β (S9) and β-catenin (S675), promoting β-catenin nuclear translocation and activating canonical WNT target genes (Cyclin D1, c-MYC, AXIN2). DVL2 knockdown or WNT inhibitor XAV-939 abrogated these effects.","method":"Co-immunoprecipitation (IFIT3/DVL isoforms), phosphorylation assays (T224-DVL2, S9-GSK3β, S675-β-catenin), β-catenin nuclear fractionation, luciferase reporter (TCF/β-catenin), siRNA knockdown of DVL2, XAV-939 pharmacological inhibition, in vivo tumor models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with defined phosphorylation events, epistasis via KD and pharmacological inhibition with defined transcriptional readouts; single lab","pmids":["41850400"],"is_preprint":false},{"year":2024,"finding":"IFIT3 promotes lymph node metastasis in esophageal squamous cell carcinoma by interacting with LASP1, facilitating LASP1 localization to the cell edge, promoting LASP1-Talin1 interaction and Talin1-integrin binding, and ultimately activating the FAK-ERK signaling pathway.","method":"Co-immunoprecipitation (IFIT3/LASP1/Talin1), confocal microscopy for subcellular localization, knockdown/overexpression, FAK-ERK phosphorylation assays, in vivo metastasis models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying binding partners with subcellular localization experiments and defined signaling readout; single lab","pmids":["41413015"],"is_preprint":false},{"year":2024,"finding":"IFIT3 selectively promotes M1 polarization of microglia and macrophages by activating STAT1 and NF-κB signaling pathways. Knockdown of IFIT3 inhibited M1 polarization without affecting M2 polarization, and ameliorated disease progression in EAE mice.","method":"siRNA knockdown, flow cytometry for M1/M2 markers, Western blot for pSTAT1 and NF-κB, AAV-mediated IFIT3 silencing in EAE mouse model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD in vitro and in vivo with defined polarization readouts and signaling pathway measurements; single lab","pmids":["38232539"],"is_preprint":false},{"year":2024,"finding":"IFIT3 interacts with and modulates STAT1 in prostate cancer small extracellular vesicles (sEVs): loss of IFIT3 generates sEVs enriched in STAT1 while reducing cellular STAT1 levels, revealing a regulatory relationship between IFIT3 and STAT1 compartmentalization in intercellular communication.","method":"CRISPR/Cas9 knockdown of IFIT3, β6 integrin subunit, or STAT1; sEV isolation; Western blot for IFIT3 and STAT1 in cells and sEVs","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization/compartmentalization finding without direct binding or pathway mechanism established; single lab, single method approach","pmids":["34622927"],"is_preprint":false},{"year":2024,"finding":"IFIT3 promotes the phosphorylation of TBK1 and STAT1 and upregulates IFN-β and ISG transcription during TGEV (porcine coronavirus) infection. Co-immunoprecipitation confirmed IFIT3 interaction with both TBK1 and STAT1; blocking the JAK-STAT1 pathway reversed IFIT3-mediated restriction of TGEV infection.","method":"Immunoprecipitation (IFIT3/TBK1 and IFIT3/STAT1), TBK1/STAT1 phosphorylation assays, overexpression/knockdown, JAK-STAT1 pathway inhibitor epistasis, viral replication assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with two binding partners, pharmacological epistasis, and defined signaling readouts; single lab, porcine cell context","pmids":["40381424"],"is_preprint":false},{"year":2023,"finding":"SARS-CoV-2 NSP16 2'-O-methyltransferase activity protects viral mRNAs from restriction by IFIT1 and IFIT3. Silencing either IFIT1 or IFIT3 partially restored fitness to the NSP16-deficient SARS-CoV-2 mutant, demonstrating that IFIT3 senses the absence of 2'-O-methylation on viral RNA caps.","method":"SARS-CoV-2 NSP16 active-site mutation, siRNA knockdown of IFIT1/IFIT3, viral replication assays in vitro, hamster model in vivo, IFN-I sensitivity assays, sinefungin (MTase inhibitor) treatment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with engineered viral mutant and siRNA KD, confirmed in vitro and in vivo, replicated with pharmacological approach","pmids":["36722972"],"is_preprint":false},{"year":2010,"finding":"IFIT3 (the most upregulated gene under antiviral conditions in Daudi cells) contributes to IFN-α antiviral activity: IFIT3-siRNA knockdown reduced IFN-α-induced antiviral protection, and IFIT3 overexpression decreased viral titers.","method":"siRNA knockdown, overexpression, antiviral assay (viral titer measurement), antibody neutralization, microarray analysis","journal":"Journal of virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD/OE with antiviral readout but no molecular mechanism identified beyond gene expression; single lab","pmids":["20686046"],"is_preprint":false}],"current_model":"IFIT3 is an interferon-induced TPR-domain protein that functions as a multivalent scaffold in innate immune signaling and antiviral defense: it bridges MAVS and TBK1 (via its TPR motif interacting with TBK1 K38) to promote IRF3 phosphorylation; it binds STING and TBK1 downstream of cGAS/STING and USP18 (stabilizing STING); it heterodimerizes with IFIT1 (via a YxxxL motif and its C-terminal domain) to allosterically restrict IFIT1's RNA-binding channel to cap 0 viral RNAs and to protect IFIT1 from proteasomal degradation, preventing self-targeting; it forms a domain-swapped heterodimer with IFIT2 that recognizes viral mRNAs bearing short 5' UTRs (<50 nt) and inhibits their translation; it directly binds RNA (including m6A-modified RNA via TPR1-2 and a helical hairpin between TPR6-7); it interacts with STAT1 and STAT2 to enhance STAT1-STAT2 heterodimerization and nuclear translocation; it binds JAB1/CSN5 to disrupt the COP9 signalosome and modulate SCF-E3 ligase activity; it is ubiquitinated by UBE2O at K236 for proteasomal degradation; and in cancer contexts it interacts with partners including VDAC2 (promoting OGT-mediated O-GlcNAcylation), ANXA2 (promoting EGFR recycling), LASP1 (activating FAK-ERK), and DVL2 (activating canonical WNT signaling)."},"narrative":{"mechanistic_narrative":"IFIT3 is an interferon-induced TPR-domain protein that functions as a multivalent scaffold coordinating innate immune signaling and direct antiviral effector activity [PMID:21813773, PMID:29554348]. In RNA-sensing signaling it bridges MAVS and TBK1, with its TPR motif (E164/E165) contacting the TBK1 N-terminus (K38) to promote TBK1 activation and IRF3 phosphorylation [PMID:21813773]; downstream of cGAS, it binds STING and TBK1 to drive IFNβ expression [PMID:29806091] and acts as a bridge between STING and the deubiquitinase USP18 to block STING degradation and amplify inflammatory signaling [PMID:41686220]. IFIT3 also potentiates the IFN-α effector arm by binding STAT1 and STAT2 to enhance STAT1–STAT2 heterodimerization and nuclear translocation and ISG induction [PMID:28295457, PMID:36314949]. As a direct effector, IFIT3 partners with the other IFITs: it heterodimerizes with IFIT1 through a C-terminal YxxxL motif, stabilizing IFIT1 against proteasomal degradation and allosterically reshaping the IFIT1 RNA-binding channel to sharpen specificity for cap-0 (2'-O-unmethylated) viral RNA [PMID:29525521, PMID:29554348, PMID:bio_10.1101_2025.11.17.688928], a sensing function confirmed against 2'-O-methyltransferase-deficient SARS-CoV-2 [PMID:36722972]; in a domain-swapped heterodimer with IFIT2 it recognizes viral mRNAs bearing short (<50 nt) 5' UTRs and inhibits their translation [PMID:41093992]. IFIT3 binds RNA directly through a conserved surface and TPR-resident elements, a property separable from dimerization and required for its RNA-dependent activities [PMID:40497724, PMID:41929069]. The protein is itself a regulatory target: it is ubiquitinated by UBE2O at K236 for proteasomal turnover [PMID:38129382] and is cleaved by coronaviral nsp5 main proteases at a defined site to antagonize type I IFN signaling [PMID:38289117]. Beyond antiviral defense, IFIT3 sequesters JAB1/CSN5 to perturb the COP9 signalosome and cullin-RING ligase activity, stabilizing p27 and driving G1/S arrest [PMID:17050680, PMID:23415865], and in cancer contexts engages partners including VDAC2, ANXA2, LASP1, and DVL2 to modulate apoptosis, EGFR recycling, FAK-ERK, and canonical WNT signaling [PMID:32641986, PMID:30626937, PMID:41850400, PMID:41413015].","teleology":[{"year":2006,"claim":"Established the first mechanistic role for IFIT3 outside antiviral defense, showing it controls cell cycle progression by acting on the ubiquitin/proteasome machinery.","evidence":"Co-IP, ectopic expression and proteasome inhibition in U937 cells linking IFIT3/JAB1 binding to p27 stabilization","pmids":["17050680"],"confidence":"High","gaps":["Did not define the IFIT3 residues mediating JAB1 binding","Relationship between this growth-arrest role and antiviral signaling unresolved"]},{"year":2010,"claim":"Defined how IFIT3 transcription is induced, showing it is an ISRE-driven gene amplified by but not strictly dependent on the classical JAK-STAT pathway, and confirmed its contribution to IFN-α antiviral protection.","evidence":"STAT1-deficient cell reconstitution with IRF-1/IRF-9/STAT2 perturbation and luciferase reporters; siRNA/overexpression antiviral titer assays","pmids":["21056555","20686046"],"confidence":"Medium","gaps":["The 2010 antiviral study identified no molecular mechanism for restriction","Did not distinguish IFIT3 effector versus signaling contributions"]},{"year":2011,"claim":"Answered how IFIT3 links upstream sensing to kinase activation, identifying it as a scaffold that physically bridges MAVS and TBK1 to promote IRF3 phosphorylation.","evidence":"Reciprocal Co-IP with E164/E165 and TBK1 K38 mutagenesis, siRNA knockdown, and IRF3 phosphorylation/antiviral assays","pmids":["21813773"],"confidence":"High","gaps":["Did not address whether the same TPR surface engages STING-pathway components","Stoichiometry within the MAVS complex not defined"]},{"year":2013,"claim":"Extended IFIT3's effect on the ubiquitin system, showing it disrupts COP9 signalosome integrity and thereby deregulates cullin-RING ligase activity and IκBα turnover.","evidence":"Co-IP, deneddylation/ubiquitination assays and Western blot of CSN subunits/Cul1/βTrCP after ectopic IFIT3 expression","pmids":["23415865"],"confidence":"Medium","gaps":["No mutagenesis to define the IFIT3 surface disrupting CSN","Reliance on overexpression leaves physiological relevance open"]},{"year":2017,"claim":"Showed IFIT3 acts on the IFN effector limb, binding STAT1 and STAT2 to enhance their heterodimerization and nuclear translocation.","evidence":"Reciprocal Co-IP, nuclear fractionation, and KD/OE with antitumor assays in HCC cells","pmids":["28295457"],"confidence":"Medium","gaps":["Did not map the STAT-binding region of IFIT3","Direct versus indirect nature of the STAT interaction not resolved"]},{"year":2018,"claim":"Resolved the structural and regulatory basis of IFIT1–IFIT3 partnership, showing IFIT3's C-terminal domain stabilizes IFIT1 and allosterically reshapes its channel to enforce cap-0 RNA specificity.","evidence":"X-ray crystallography of cap-0 RNA–IFIT1–IFIT3 CTD with binding, half-life and viral restriction assays; in vitro IFIT complex reconstitution with YxxxL mutagenesis and EMSA","pmids":["29525521","29554348"],"confidence":"High","gaps":["Mouse Ifit3 lacks the relevant CTD, complicating model-organism extrapolation","How IFIT2/IFIT3 versus IFIT1/IFIT3 complex choice is governed not defined here"]},{"year":2018,"claim":"Placed IFIT3 within the cytosolic DNA-sensing pathway, showing it interacts with STING and TBK1 to drive IFNβ downstream of cGAS/STING.","evidence":"Co-IP of IFIT3 with STING and TBK1 and gain/loss-of-function IFNβ assays in human monocytes","pmids":["29806091"],"confidence":"Medium","gaps":["Interaction interfaces with STING/TBK1 not mapped","Whether STING and MAVS scaffolding use the same IFIT3 surface unknown"]},{"year":2023,"claim":"Identified the degradation control of IFIT3 itself, defining UBE2O-mediated ubiquitination at K236 as a checkpoint limiting IFN-α efficacy.","evidence":"MS, Co-IP, K236A mutagenesis rescue and KD/OE functional assays in hepatocellular carcinoma","pmids":["38129382"],"confidence":"Medium","gaps":["E3 ligase cooperating with UBE2O not identified","Signals triggering IFIT3 degradation undefined"]},{"year":2024,"claim":"Revealed a viral evasion strategy targeting IFIT3, showing coronaviral nsp5 proteases cleave it at a defined residue to disable type I IFN signaling.","evidence":"In vitro cleavage assays with Q406A mutagenesis across multiple coronavirus nsp5 proteins and viral replication assays","pmids":["38289117"],"confidence":"High","gaps":["Functional consequence of cleavage fragments not characterized","Whether cleavage abolishes scaffolding or effector functions selectively unresolved"]},{"year":2025,"claim":"Defined IFIT3's intrinsic RNA-binding activity and its targets, showing direct RNA binding through a conserved surface and TPR elements, separable from dimerization and including preferential m6A-modified RNA recognition.","evidence":"Cryo-EM of the domain-swapped IFIT2-IFIT3 heterodimer with translation assays; EMSA/RBS-ID mutagenesis for IAV; HyperTRIBE-seq and TPR/hairpin mutagenesis for m6A/HCV RNA (preprint)","pmids":["41093992","40497724","41929069"],"confidence":"High","gaps":["Pro-viral versus antiviral outcomes of IFIT3 RNA binding context-dependent and not unified","m6A-dependence characterized only in preprint form"]},{"year":2025,"claim":"Showed why IFIT1 accumulation is coupled to IFIT3, demonstrating that IFIT3 protects IFIT1 from degradation and rescues self ISG mRNAs from IFIT1-mediated translation inhibition, preventing self-targeting.","evidence":"Ectopic IFIT1±IFIT3 expression, proteasome inhibition, translation and viral replication assays (preprint)","pmids":["bio_10.1101_2025.11.17.688928"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Quantitative thresholds distinguishing self versus viral RNA discrimination undefined"]},{"year":2026,"claim":"Refined IFIT3's role in STING signaling, showing it bridges STING and USP18 to block STING ubiquitination and amplify inflammatory output.","evidence":"Co-IP of the IFIT3/STING/USP18 complex, ubiquitination assays and AAV-mediated in vivo knockdown affecting lung injury and M1 polarization","pmids":["41686220"],"confidence":"Medium","gaps":["Direct versus bridged contacts within the ternary complex partially inferred","Whether USP18 acts catalytically or stoichiometrically on STING not resolved"]},{"year":null,"claim":"How IFIT3 partitions between its many roles — antiviral effector, signaling scaffold, and pro-tumorigenic partner — and what determines which complexes (IFIT1, IFIT2, STING/TBK1, STAT, VDAC2, ANXA2, LASP1, DVL2) it forms in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling antiviral and pro-viral/pro-tumor activities","Determinants of complex selection in vivo unknown","Most cancer-context partners rest on single-lab Co-IP without structural validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11,12,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,22]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[24]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,7,16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,6,23,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,11,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]}],"complexes":["IFIT1-IFIT3 heterodimer","IFIT2-IFIT3 heterodimer","COP9 signalosome (disrupts)"],"partners":["TBK1","STING","IFIT1","IFIT2","STAT1","STAT2","USP18","JAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14879","full_name":"Interferon-induced protein with tetratricopeptide repeats 3","aliases":["CIG49","ISG-60","Interferon-induced 60 kDa protein","IFI-60K","Interferon-induced protein with tetratricopeptide repeats 4","IFIT-4","Retinoic acid-induced gene G protein","P60","RIG-G"],"length_aa":490,"mass_kda":56.0,"function":"IFN-induced antiviral protein which acts as an inhibitor of cellular as well as viral processes, cell migration, proliferation, signaling, and viral replication. 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Can negatively regulate the apoptotic effects of IFIT2","subcellular_location":"Cytoplasm; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O14879/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFIT3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFIT3","total_profiled":1310},"omim":[{"mim_id":"618648","title":"IMMUNODEFICIENCY 65, SUSCEPTIBILITY TO VIRAL INFECTIONS; IMD65","url":"https://www.omim.org/entry/618648"},{"mim_id":"604650","title":"INTERFERON-INDUCED PROTEIN WITH TETRATRICOPEPTIDE REPEATS 3; IFIT3","url":"https://www.omim.org/entry/604650"},{"mim_id":"147574","title":"INTERFERON REGULATORY FACTOR 9; IRF9","url":"https://www.omim.org/entry/147574"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Disruption of this interaction attenuates TBK1 and IRF3 activation.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression, siRNA knockdown, mutagenesis (E164/E165 and K38), IRF3 phosphorylation assays, antiviral replication assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with defined interaction residues confirmed by mutagenesis, functional epistasis via KD/OE with defined signaling readouts, replicated in multiple cell systems\",\n      \"pmids\": [\"21813773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of cap 0 RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3 reveals that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending IFIT1 half-life (increasing steady-state protein levels) and (2) allosterically reshaping the IFIT1 RNA-binding channel to enhance specificity for cap 0 but not cap 1 or 5'-ppp RNA. Mouse Ifit3 lacks this C-terminal domain and does not bind mouse Ifit1.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, mutagenesis, cell-based half-life/stability assays, viral restriction assays with 2'-O methylation-deficient viruses\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, mutagenesis, multiple orthogonal biochemical methods in a single rigorous study\",\n      \"pmids\": [\"29525521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFIT1 and IFIT3 interact via a conserved YxxxL motif in the C-terminus of each protein. IFIT2 and IFIT3 homodimers dissociate to form a more stable heterodimer that also associates with IFIT1. IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to cap0 Zika virus reporter mRNA, and enhances IFIT1-mediated translation inhibition.\",\n      \"method\": \"In vitro reconstitution of IFIT complexes, electrophoretic mobility shift assays (EMSA), mutagenesis (YxxxL motif), translation inhibition assays, protein stability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, multiple orthogonal functional assays; independently corroborates PMID:29525521\",\n      \"pmids\": [\"29554348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RIG-G (IFIT3) induces G1/S cell cycle arrest by interacting with JAB1 (CSN5), sequestering it and preventing JAB1-dependent, ubiquitin/proteasome-mediated degradation of p27, thereby elevating p27 levels. Additionally, RIG-G causes c-Myc downregulation, leading to p21 upregulation, contributing to growth arrest.\",\n      \"method\": \"Ectopic expression in U937 cells, Co-immunoprecipitation (RIG-G/JAB1 interaction), cell cycle analysis (flow cytometry), Western blot for p21/p27/c-Myc, ubiquitin/proteasome inhibition experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for binding partner, mechanistic dissection of p27 degradation pathway with multiple readouts in a single rigorous study\",\n      \"pmids\": [\"17050680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RIG-G (IFIT3) disrupts the integrity and stability of the COP9 signalosome (CSN) complex, dramatically reducing cellular CSN content and inhibiting its regulatory roles in assembly and activation of cullin-RING ubiquitin E3 ligases (CRL). This causes excessive CRL activation (via CSN-mediated deneddylation inhibition), decreasing Cul1 and βTrCP levels, and impairing CSN-associated deubiquitination (USP15 recruitment), resulting in accumulation of IκBα.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for CSN subunits/Cul1/βTrCP/IκBα, deneddylation assays, ubiquitination assays, ectopic expression of RIG-G\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays in a single lab, ectopic expression approach without full mutagenesis validation\",\n      \"pmids\": [\"23415865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IFIT3 binds STAT1 and STAT2 to enhance STAT1-STAT2 heterodimerization and nuclear translocation upon IFN-α treatment, thereby promoting IFN-α effector signaling. This was demonstrated by co-immunoprecipitation in HCC cells and confirmed functionally in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (IFIT3/STAT1 and IFIT3/STAT2), nuclear fractionation, ectopic expression and knockdown, in vitro and in vivo antitumor assays\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional epistasis (KD/OE), single lab, mechanistic follow-up included\",\n      \"pmids\": [\"28295457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFIT3 interacts with both STING and TBK1, and promotes IFNβ expression downstream of the cGAS/STING pathway. Knockdown of IFIT3 reduced VACV70-induced IFNβ expression, while overexpression produced an opposite effect.\",\n      \"method\": \"Co-immunoprecipitation (IFIT3/STING and IFIT3/TBK1), gain- and loss-of-function experiments, IFNβ expression assays in human monocytes\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating two binding partners, functional KD/OE with defined readout, single lab\",\n      \"pmids\": [\"29806091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFIT3 directly interacts with the mitochondrial channel protein VDAC2, and stabilizes the interaction of VDAC2 with O-GlcNAc transferase (OGT), promoting O-GlcNAcylation of VDAC2. This increased VDAC2 O-GlcNAcylation protects PDAC cells from chemotherapy-induced apoptosis, conferring drug resistance.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, subcellular fractionation, confocal immunofluorescence, knockdown/overexpression, apoptosis assays, chromatin-immunoprecipitation\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and MS identified interaction, post-translational modification mechanism characterized, multiple functional assays; single lab\",\n      \"pmids\": [\"32641986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFIT1 and IFIT3 interact with ANXA2 (Annexin A2) by co-immunoprecipitation and LC-MS/MS, and this interaction enhances endosomal recycling of phosphorylated EGFR (p-EGFRY1068). Depletion of ANXA2 abolished p-EGFR and p-AKT expression in IFIT1- or IFIT3-overexpressing OSCC cells.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, siRNA knockdown of ANXA2, Western blot for p-EGFR/p-AKT, xenograft and orthotopic mouse models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS for binding partner identification, epistasis via ANXA2 knockdown with defined signaling readout, single lab\",\n      \"pmids\": [\"30626937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2O ubiquitinates IFIT3 at lysine 236 (K236), targeting it for proteasomal degradation and reducing IFN-α signaling efficacy in hepatocellular carcinoma. Knockdown of UBE2O increased IFIT3 expression and enhanced IFN-α antitumor effects; rescue experiments with K236 mutant IFIT3 confirmed dependence on this ubiquitination site.\",\n      \"method\": \"Proteomic analysis, mass spectrometry, co-immunoprecipitation, mutagenesis (K236A), knockdown/overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site identified by MS with mutagenesis rescue validation, multiple functional assays, single lab\",\n      \"pmids\": [\"38129382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDCoV nsp5 (main protease) cleaves porcine IFIT3 at Gln-406, antagonizing type I interferon signaling. A pIFIT3-Q406A mutant was resistant to nsp5-mediated cleavage and exhibited greater ability to inhibit PDCoV infection than wild-type IFIT3. Similar cleavage of endogenous IFIT3 by nsp5 proteins of multiple human coronaviruses (but not alphacoronaviruses) was observed.\",\n      \"method\": \"Transcriptomic analysis, site-directed mutagenesis (Q406A), in vitro cleavage assays, ectopic expression, viral replication assays, Western blot\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro cleavage assay with mutagenesis validation at defined cleavage site, multiple viral contexts tested, functional consequence demonstrated\",\n      \"pmids\": [\"38289117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The IFIT2-IFIT3 heterodimer, formed through a domain-swapped structure resolved by cryo-EM at 3.2 Å, recognizes viral mRNA 5' ends with short untranslated regions (<50 nucleotides) as a molecular pattern, inhibiting their translation. This complex mediates antiviral activity against viruses with short 5' UTRs (e.g., VSV, parainfluenza virus 3).\",\n      \"method\": \"Cryo-EM structure determination (3.2 Å), in vitro translation inhibition assays, mutagenesis, viral replication assays\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation, in vitro translation assays, multiple viral systems tested\",\n      \"pmids\": [\"41093992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFIT3 directly binds RNA via a conserved surface composed of residues shared with IFIT2 paralogs, located near the dimerization interface. Mutation of this RNA-binding surface reduced IFIT3's ability to promote IAV gene expression and translation efficiency without affecting IFIT2/IFIT3 dimerization, establishing that RNA binding is functionally separable from dimerization and required for pro-viral activity during IAV infection.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), RNA-binding site identification (RBS-ID), mutagenesis, co-immunoprecipitation, IAV replication/translation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct RNA binding validated by EMSA, binding site identified and mutated with functional consequence for translation and replication, dimerization separability demonstrated by Co-IP\",\n      \"pmids\": [\"40497724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFIT3 mediates TBK1 phosphorylation as an upstream regulatory factor, activating plasmacytoid dendritic cells (pDCs) and contributing to SSc pathogenesis. IFIT3-knockout mice showed reduced skin and lung fibrosis in the SSc model.\",\n      \"method\": \"Single-cell RNA sequencing, in vitro cell experiments, CRISPR/Cas9 IFIT3-knockout mouse model, TBK1 phosphorylation assays, cytokine measurements\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with in vitro mechanistic follow-up (TBK1 phosphorylation), single lab\",\n      \"pmids\": [\"39305055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFIT3 promotes the anti-HBV effect of IFN-α in a STAT2-dependent manner: knockdown of IFIT3 inhibited STAT2 phosphorylation while overexpression promoted it, and IFIT3 overexpression enhanced IFN-α-triggered ISG expression (MxA, OAS1, PKR). This effect was abrogated by JAK inhibitor ruxolitinib.\",\n      \"method\": \"shRNA knockdown, overexpression, Western blot for pSTAT2, qRT-PCR for ISGs, HBV antigen/DNA quantification, ruxolitinib epistasis experiment\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined signaling readout and epistasis via pharmacological JAK inhibition, single lab\",\n      \"pmids\": [\"36314949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HSV-1 tegument protein UL41, a viral endoribonuclease, counteracts IFIT3 antiviral activity by degrading IFIT3 mRNA, reducing its accumulation. UL41-null mutant HSV-1 replication was restricted by ectopic IFIT3, and stable IFIT3 knockdown facilitated UL41-null virus replication.\",\n      \"method\": \"Ectopic expression of UL41, UL41-null mutant virus (R2621), stable IFIT3 knockdown, mRNA quantification, viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis using null mutant virus with complementary KD/OE experiments, mechanism at mRNA level demonstrated, single lab\",\n      \"pmids\": [\"27681138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFIT1 and IFIT3 form a complex with BAX and N-GSDME, directing N-GSDME translocation to mitochondria and increasing mitochondrial membrane permeabilization, thereby triggering pyroptosis in myeloma and leukemia cells.\",\n      \"method\": \"Co-immunoprecipitation, RNA sequencing, siRNA knockdown, caspase/GSDME activation assays, mitochondrial fractionation, venetoclax combination experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying multi-protein complex, subcellular fractionation showing mitochondrial translocation, KD with functional readout; single lab\",\n      \"pmids\": [\"38462032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBV regulatory protein HBx activates NF-κB, which in turn directly drives IFIT3 transcription, and overexpressed IFIT3 paradoxically enhances HBV replication in HepG2 cells.\",\n      \"method\": \"Transfection with pHBV1.3 plasmid, NF-κB activation assays, IFIT3 overexpression, HBV replication assays\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic link between NF-κB and IFIT3 transcription implied but not confirmed by direct promoter binding assay in this abstract; functional consequence demonstrated\",\n      \"pmids\": [\"31681236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFIT3 (ISG60) constitutes a negative feedback loop downstream of TLR3/IFN-β signaling in brain capillary endothelial cells: knockdown of IFIT3 increased poly IC-induced IFN-β and CXCL10 expression, demonstrating that IFIT3 limits these responses.\",\n      \"method\": \"siRNA knockdown of ISG60, poly IC treatment, ELISA/qRT-PCR for IFN-β and CXCL10\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single KD experiment with defined readout, single lab, no binding partner or molecular mechanism identified\",\n      \"pmids\": [\"30195920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFIT3 shows binding to JNK and STAT1 in pancreatic cancer cells (COLO357FG), and STAT1 is an important inducer of IFIT3 expression. Transgenic IFIT3 expression increased VEGF and IL-6 secretion, chemoresistance, and decreased starvation-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (IFIT3/JNK and IFIT3/STAT1), ectopic expression, in vitro/in vivo tumor assays, cytokine quantification\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying binding partners, functional follow-up present but mechanism not fully resolved, single lab\",\n      \"pmids\": [\"25650658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"STAT1 significantly enhances the IRF-9/STAT2 complex or IRF-1 on RIG-G (IFIT3) induction through the activated JAK-STAT pathway; however, STAT1 is not essential for RIG-G expression. In STAT1-deficient cells, IRF-1 can induce RIG-G expression via ISREs, but cannot upregulate IRF-9 and STAT2 unless STAT1 is reconstituted. RIG-G expression is independent of the classical JAK-STAT pathway but greatly amplified by it.\",\n      \"method\": \"STAT1-deficient U3A cell reconstitution, luciferase reporter assays, Western blot, IRF-1/IRF-9/STAT2 overexpression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis using isogenic STAT1-deficient cell reconstitution system, multiple transcription factor perturbations with defined readout; single lab\",\n      \"pmids\": [\"21056555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFIT3 preferentially associates with N6-methyladenosine (m6A)-modified HCV genomic RNA and host transcripts to restrict HCV infection. Two structural regions are required for RNA binding: TPR1-2 (required for IFIT2 interaction but dispensable for HCV RNA binding) and a predicted helical hairpin between TPR6 and TPR7 (required for HCV RNA binding but dispensable for IFIT2 interaction). Loss of either region diminished antiviral activity.\",\n      \"method\": \"HyperTRIBE-seq (transcriptome-wide RNA-binding site mapping), co-purification with m6A-modified RNA probes, m6A inhibition experiments, mutagenesis of TPR domains and helical hairpin, HCV replication assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (HyperTRIBE, biochemical binding, mutagenesis, functional assays) in a single preprint; not yet peer-reviewed\",\n      \"pmids\": [\"41929069\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"When IFIT1 is expressed at high levels without IFIT3, it can inhibit translation of certain self ISG mRNAs (including ISG15 and IFITM1). IFIT1:IFIT3 complex formation rescues these self-ISGs from IFIT1-mediated translation inhibition. IFIT3 directly binds IFIT1 and protects it from proteasomal degradation, ensuring IFIT1 accumulation only occurs alongside IFIT3—a mechanism to prevent self-targeting while enabling antiviral activity.\",\n      \"method\": \"Ectopic expression of IFIT1 with/without IFIT3, siRNA knockdown, proteasome inhibitor experiments, translation assays, viral replication assays (Semliki Forest virus)\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and proteasomal degradation mechanism with multiple functional readouts; preprint not yet peer-reviewed, but mechanistically detailed\",\n      \"pmids\": [\"bio_10.1101_2025.11.17.688928\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IFIT3 acts as a molecular bridge between STING and the deubiquitinase USP18, inhibiting ubiquitination-mediated degradation of STING and amplifying downstream cGAS-STING inflammatory signaling. IFIT3 promoted M1 macrophage polarization and early lung injury; IFIT3 knockdown ameliorated early lung injury in vivo.\",\n      \"method\": \"Co-immunoprecipitation (IFIT3/STING/USP18), ubiquitination assays, IFIT3 knockdown in vivo (AAV-mediated), flow cytometry for M1/M2 polarization, cytokine assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining ternary complex with functional epistasis via in vivo KD; single lab, mechanism partially inferred\",\n      \"pmids\": [\"41686220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFIT3 interacts with DVL2 (dishevelled 2) in the cytoplasm of lung squamous cell carcinoma cells and promotes phosphorylation of DVL2 at threonine 224, increasing phosphorylation of GSK-3β (S9) and β-catenin (S675), promoting β-catenin nuclear translocation and activating canonical WNT target genes (Cyclin D1, c-MYC, AXIN2). DVL2 knockdown or WNT inhibitor XAV-939 abrogated these effects.\",\n      \"method\": \"Co-immunoprecipitation (IFIT3/DVL isoforms), phosphorylation assays (T224-DVL2, S9-GSK3β, S675-β-catenin), β-catenin nuclear fractionation, luciferase reporter (TCF/β-catenin), siRNA knockdown of DVL2, XAV-939 pharmacological inhibition, in vivo tumor models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with defined phosphorylation events, epistasis via KD and pharmacological inhibition with defined transcriptional readouts; single lab\",\n      \"pmids\": [\"41850400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFIT3 promotes lymph node metastasis in esophageal squamous cell carcinoma by interacting with LASP1, facilitating LASP1 localization to the cell edge, promoting LASP1-Talin1 interaction and Talin1-integrin binding, and ultimately activating the FAK-ERK signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation (IFIT3/LASP1/Talin1), confocal microscopy for subcellular localization, knockdown/overexpression, FAK-ERK phosphorylation assays, in vivo metastasis models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying binding partners with subcellular localization experiments and defined signaling readout; single lab\",\n      \"pmids\": [\"41413015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFIT3 selectively promotes M1 polarization of microglia and macrophages by activating STAT1 and NF-κB signaling pathways. Knockdown of IFIT3 inhibited M1 polarization without affecting M2 polarization, and ameliorated disease progression in EAE mice.\",\n      \"method\": \"siRNA knockdown, flow cytometry for M1/M2 markers, Western blot for pSTAT1 and NF-κB, AAV-mediated IFIT3 silencing in EAE mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD in vitro and in vivo with defined polarization readouts and signaling pathway measurements; single lab\",\n      \"pmids\": [\"38232539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFIT3 interacts with and modulates STAT1 in prostate cancer small extracellular vesicles (sEVs): loss of IFIT3 generates sEVs enriched in STAT1 while reducing cellular STAT1 levels, revealing a regulatory relationship between IFIT3 and STAT1 compartmentalization in intercellular communication.\",\n      \"method\": \"CRISPR/Cas9 knockdown of IFIT3, β6 integrin subunit, or STAT1; sEV isolation; Western blot for IFIT3 and STAT1 in cells and sEVs\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization/compartmentalization finding without direct binding or pathway mechanism established; single lab, single method approach\",\n      \"pmids\": [\"34622927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFIT3 promotes the phosphorylation of TBK1 and STAT1 and upregulates IFN-β and ISG transcription during TGEV (porcine coronavirus) infection. Co-immunoprecipitation confirmed IFIT3 interaction with both TBK1 and STAT1; blocking the JAK-STAT1 pathway reversed IFIT3-mediated restriction of TGEV infection.\",\n      \"method\": \"Immunoprecipitation (IFIT3/TBK1 and IFIT3/STAT1), TBK1/STAT1 phosphorylation assays, overexpression/knockdown, JAK-STAT1 pathway inhibitor epistasis, viral replication assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with two binding partners, pharmacological epistasis, and defined signaling readouts; single lab, porcine cell context\",\n      \"pmids\": [\"40381424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SARS-CoV-2 NSP16 2'-O-methyltransferase activity protects viral mRNAs from restriction by IFIT1 and IFIT3. Silencing either IFIT1 or IFIT3 partially restored fitness to the NSP16-deficient SARS-CoV-2 mutant, demonstrating that IFIT3 senses the absence of 2'-O-methylation on viral RNA caps.\",\n      \"method\": \"SARS-CoV-2 NSP16 active-site mutation, siRNA knockdown of IFIT1/IFIT3, viral replication assays in vitro, hamster model in vivo, IFN-I sensitivity assays, sinefungin (MTase inhibitor) treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with engineered viral mutant and siRNA KD, confirmed in vitro and in vivo, replicated with pharmacological approach\",\n      \"pmids\": [\"36722972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IFIT3 (the most upregulated gene under antiviral conditions in Daudi cells) contributes to IFN-α antiviral activity: IFIT3-siRNA knockdown reduced IFN-α-induced antiviral protection, and IFIT3 overexpression decreased viral titers.\",\n      \"method\": \"siRNA knockdown, overexpression, antiviral assay (viral titer measurement), antibody neutralization, microarray analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD/OE with antiviral readout but no molecular mechanism identified beyond gene expression; single lab\",\n      \"pmids\": [\"20686046\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFIT3 is an interferon-induced TPR-domain protein that functions as a multivalent scaffold in innate immune signaling and antiviral defense: it bridges MAVS and TBK1 (via its TPR motif interacting with TBK1 K38) to promote IRF3 phosphorylation; it binds STING and TBK1 downstream of cGAS/STING and USP18 (stabilizing STING); it heterodimerizes with IFIT1 (via a YxxxL motif and its C-terminal domain) to allosterically restrict IFIT1's RNA-binding channel to cap 0 viral RNAs and to protect IFIT1 from proteasomal degradation, preventing self-targeting; it forms a domain-swapped heterodimer with IFIT2 that recognizes viral mRNAs bearing short 5' UTRs (<50 nt) and inhibits their translation; it directly binds RNA (including m6A-modified RNA via TPR1-2 and a helical hairpin between TPR6-7); it interacts with STAT1 and STAT2 to enhance STAT1-STAT2 heterodimerization and nuclear translocation; it binds JAB1/CSN5 to disrupt the COP9 signalosome and modulate SCF-E3 ligase activity; it is ubiquitinated by UBE2O at K236 for proteasomal degradation; and in cancer contexts it interacts with partners including VDAC2 (promoting OGT-mediated O-GlcNAcylation), ANXA2 (promoting EGFR recycling), LASP1 (activating FAK-ERK), and DVL2 (activating canonical WNT signaling).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFIT3 is an interferon-induced TPR-domain protein that functions as a multivalent scaffold coordinating innate immune signaling and direct antiviral effector activity [#0, #2]. In RNA-sensing signaling it bridges MAVS and TBK1, with its TPR motif (E164/E165) contacting the TBK1 N-terminus (K38) to promote TBK1 activation and IRF3 phosphorylation [#0]; downstream of cGAS, it binds STING and TBK1 to drive IFNβ expression [#6] and acts as a bridge between STING and the deubiquitinase USP18 to block STING degradation and amplify inflammatory signaling [#23]. IFIT3 also potentiates the IFN-α effector arm by binding STAT1 and STAT2 to enhance STAT1–STAT2 heterodimerization and nuclear translocation and ISG induction [#5, #14]. As a direct effector, IFIT3 partners with the other IFITs: it heterodimerizes with IFIT1 through a C-terminal YxxxL motif, stabilizing IFIT1 against proteasomal degradation and allosterically reshaping the IFIT1 RNA-binding channel to sharpen specificity for cap-0 (2'-O-unmethylated) viral RNA [#1, #2, #22], a sensing function confirmed against 2'-O-methyltransferase-deficient SARS-CoV-2 [#29]; in a domain-swapped heterodimer with IFIT2 it recognizes viral mRNAs bearing short (<50 nt) 5' UTRs and inhibits their translation [#11]. IFIT3 binds RNA directly through a conserved surface and TPR-resident elements, a property separable from dimerization and required for its RNA-dependent activities [#12, #21]. The protein is itself a regulatory target: it is ubiquitinated by UBE2O at K236 for proteasomal turnover [#9] and is cleaved by coronaviral nsp5 main proteases at a defined site to antagonize type I IFN signaling [#10]. Beyond antiviral defense, IFIT3 sequesters JAB1/CSN5 to perturb the COP9 signalosome and cullin-RING ligase activity, stabilizing p27 and driving G1/S arrest [#3, #4], and in cancer contexts engages partners including VDAC2, ANXA2, LASP1, and DVL2 to modulate apoptosis, EGFR recycling, FAK-ERK, and canonical WNT signaling [#7, #8, #24, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first mechanistic role for IFIT3 outside antiviral defense, showing it controls cell cycle progression by acting on the ubiquitin/proteasome machinery.\",\n      \"evidence\": \"Co-IP, ectopic expression and proteasome inhibition in U937 cells linking IFIT3/JAB1 binding to p27 stabilization\",\n      \"pmids\": [\"17050680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the IFIT3 residues mediating JAB1 binding\", \"Relationship between this growth-arrest role and antiviral signaling unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined how IFIT3 transcription is induced, showing it is an ISRE-driven gene amplified by but not strictly dependent on the classical JAK-STAT pathway, and confirmed its contribution to IFN-α antiviral protection.\",\n      \"evidence\": \"STAT1-deficient cell reconstitution with IRF-1/IRF-9/STAT2 perturbation and luciferase reporters; siRNA/overexpression antiviral titer assays\",\n      \"pmids\": [\"21056555\", \"20686046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The 2010 antiviral study identified no molecular mechanism for restriction\", \"Did not distinguish IFIT3 effector versus signaling contributions\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Answered how IFIT3 links upstream sensing to kinase activation, identifying it as a scaffold that physically bridges MAVS and TBK1 to promote IRF3 phosphorylation.\",\n      \"evidence\": \"Reciprocal Co-IP with E164/E165 and TBK1 K38 mutagenesis, siRNA knockdown, and IRF3 phosphorylation/antiviral assays\",\n      \"pmids\": [\"21813773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether the same TPR surface engages STING-pathway components\", \"Stoichiometry within the MAVS complex not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended IFIT3's effect on the ubiquitin system, showing it disrupts COP9 signalosome integrity and thereby deregulates cullin-RING ligase activity and IκBα turnover.\",\n      \"evidence\": \"Co-IP, deneddylation/ubiquitination assays and Western blot of CSN subunits/Cul1/βTrCP after ectopic IFIT3 expression\",\n      \"pmids\": [\"23415865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis to define the IFIT3 surface disrupting CSN\", \"Reliance on overexpression leaves physiological relevance open\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed IFIT3 acts on the IFN effector limb, binding STAT1 and STAT2 to enhance their heterodimerization and nuclear translocation.\",\n      \"evidence\": \"Reciprocal Co-IP, nuclear fractionation, and KD/OE with antitumor assays in HCC cells\",\n      \"pmids\": [\"28295457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the STAT-binding region of IFIT3\", \"Direct versus indirect nature of the STAT interaction not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structural and regulatory basis of IFIT1–IFIT3 partnership, showing IFIT3's C-terminal domain stabilizes IFIT1 and allosterically reshapes its channel to enforce cap-0 RNA specificity.\",\n      \"evidence\": \"X-ray crystallography of cap-0 RNA–IFIT1–IFIT3 CTD with binding, half-life and viral restriction assays; in vitro IFIT complex reconstitution with YxxxL mutagenesis and EMSA\",\n      \"pmids\": [\"29525521\", \"29554348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mouse Ifit3 lacks the relevant CTD, complicating model-organism extrapolation\", \"How IFIT2/IFIT3 versus IFIT1/IFIT3 complex choice is governed not defined here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed IFIT3 within the cytosolic DNA-sensing pathway, showing it interacts with STING and TBK1 to drive IFNβ downstream of cGAS/STING.\",\n      \"evidence\": \"Co-IP of IFIT3 with STING and TBK1 and gain/loss-of-function IFNβ assays in human monocytes\",\n      \"pmids\": [\"29806091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction interfaces with STING/TBK1 not mapped\", \"Whether STING and MAVS scaffolding use the same IFIT3 surface unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the degradation control of IFIT3 itself, defining UBE2O-mediated ubiquitination at K236 as a checkpoint limiting IFN-α efficacy.\",\n      \"evidence\": \"MS, Co-IP, K236A mutagenesis rescue and KD/OE functional assays in hepatocellular carcinoma\",\n      \"pmids\": [\"38129382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase cooperating with UBE2O not identified\", \"Signals triggering IFIT3 degradation undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a viral evasion strategy targeting IFIT3, showing coronaviral nsp5 proteases cleave it at a defined residue to disable type I IFN signaling.\",\n      \"evidence\": \"In vitro cleavage assays with Q406A mutagenesis across multiple coronavirus nsp5 proteins and viral replication assays\",\n      \"pmids\": [\"38289117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of cleavage fragments not characterized\", \"Whether cleavage abolishes scaffolding or effector functions selectively unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined IFIT3's intrinsic RNA-binding activity and its targets, showing direct RNA binding through a conserved surface and TPR elements, separable from dimerization and including preferential m6A-modified RNA recognition.\",\n      \"evidence\": \"Cryo-EM of the domain-swapped IFIT2-IFIT3 heterodimer with translation assays; EMSA/RBS-ID mutagenesis for IAV; HyperTRIBE-seq and TPR/hairpin mutagenesis for m6A/HCV RNA (preprint)\",\n      \"pmids\": [\"41093992\", \"40497724\", \"41929069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pro-viral versus antiviral outcomes of IFIT3 RNA binding context-dependent and not unified\", \"m6A-dependence characterized only in preprint form\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed why IFIT1 accumulation is coupled to IFIT3, demonstrating that IFIT3 protects IFIT1 from degradation and rescues self ISG mRNAs from IFIT1-mediated translation inhibition, preventing self-targeting.\",\n      \"evidence\": \"Ectopic IFIT1±IFIT3 expression, proteasome inhibition, translation and viral replication assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.17.688928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Quantitative thresholds distinguishing self versus viral RNA discrimination undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Refined IFIT3's role in STING signaling, showing it bridges STING and USP18 to block STING ubiquitination and amplify inflammatory output.\",\n      \"evidence\": \"Co-IP of the IFIT3/STING/USP18 complex, ubiquitination assays and AAV-mediated in vivo knockdown affecting lung injury and M1 polarization\",\n      \"pmids\": [\"41686220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus bridged contacts within the ternary complex partially inferred\", \"Whether USP18 acts catalytically or stoichiometrically on STING not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFIT3 partitions between its many roles — antiviral effector, signaling scaffold, and pro-tumorigenic partner — and what determines which complexes (IFIT1, IFIT2, STING/TBK1, STAT, VDAC2, ANXA2, LASP1, DVL2) it forms in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling antiviral and pro-viral/pro-tumor activities\", \"Determinants of complex selection in vivo unknown\", \"Most cancer-context partners rest on single-lab Co-IP without structural validation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11, 12, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 22]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 7, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 6, 23, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 11, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"IFIT1-IFIT3 heterodimer\",\n      \"IFIT2-IFIT3 heterodimer\",\n      \"COP9 signalosome (disrupts)\"\n    ],\n    \"partners\": [\n      \"TBK1\",\n      \"STING\",\n      \"IFIT1\",\n      \"IFIT2\",\n      \"STAT1\",\n      \"STAT2\",\n      \"USP18\",\n      \"JAB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}