{"gene":"IFIT1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2011,"finding":"IFIT1 directly binds 5'-triphosphate RNA (PPP-RNA) with nanomolar affinity, requiring arginine at position 187 in a highly charged carboxy-terminal groove. It mediates assembly of a larger protein complex containing other IFIT family members (IFIT2, IFIT3) that sequesters viral PPP-RNA, restricting viral replication.","method":"Affinity proteomics with PPP-RNA bait, binding affinity measurements, site-directed mutagenesis (R187), Ifit1-knockout mouse infection experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding assay with mutagenesis, affinity measurements, and in vivo KO validation across multiple viral pathogens, replicated in subsequent studies","pmids":["21642987"],"is_preprint":false},{"year":2013,"finding":"IFIT1 is the sole interferon-induced protein that selectively binds 2'O-unmethylated capped RNA (cap 0) over 2'O-methylated capped RNA (cap 1). IFIT1 tethers a species-specific complex of other IFIT proteins to RNA and sequesters cap-0 RNA, thereby competitively impairing binding of eukaryotic translation initiation factors to the RNA template and inhibiting translation.","method":"Proteome-wide affinity purification coupled to mass spectrometry, pulsed SILAC-MS, in vitro competition translation assays, functional validation with viral infection models","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (AP-MS, SILAC, in vitro competition), independently replicated across multiple studies","pmids":["24098121"],"is_preprint":false},{"year":2009,"finding":"IFIT1 (ISG56) binds the adapter protein MITA (also known as STING) and disrupts interactions between MITA and the upstream signaling components VISA and TBK1, thereby inhibiting virus-triggered IRF3/NF-κB activation and type I IFN production — functioning as a negative-feedback regulator.","method":"Co-immunoprecipitation, competitive co-IP, overexpression/knockdown experiments, IFN-β promoter reporter assay, VSV replication rescue assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal co-IP and competitive co-IP with functional readout (IFN-β induction, viral replication), single lab","pmids":["19416887"],"is_preprint":false},{"year":2006,"finding":"IFIT1 (P56) and its paralog IFIT2 (P54) bind to the translation initiation factor eIF3 and inhibit translation; IFIT1 specifically binds the 'e' subunit of eIF3 and inhibits the ability of eIF3 to stabilize the eIF2·GTP·Met-tRNAi ternary complex.","method":"Co-immunoprecipitation with eIF3 subunits, in vitro translation inhibition assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with eIF3 subunits plus functional in vitro translation assay, single lab","pmids":["16973618"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of RNA-bound human IFIT1 (1.6 Å with capped RNA) reveals a water-filled, positively charged RNA-binding tunnel with a hydrophobic extension that engages the mRNA cap in multiple conformations (syn and anti). Cap-proximal nucleotides provide affinity to compete with eIF4F. N1 2'O-methylation and N2 2'O-methylation both interfere with IFIT1 binding, revealing synergistic roles for these modifications in self- vs. nonself-mRNA discrimination. Mutagenesis confirmed RNA binding is required for antiviral restriction of a coronavirus lacking N1 methylation.","method":"X-ray crystallography, gel-shift binding assays, in vitro translation assays, structure-guided mutagenesis, coronavirus infection experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional validation by mutagenesis and binding assays in a single rigorous study","pmids":["28251928"],"is_preprint":false},{"year":2018,"finding":"Human IFIT3 binds to IFIT1 via its C-terminal domain and has dual regulatory functions: (1) it extends the half-life of IFIT1, increasing its steady-state abundance; and (2) it allosterically modulates the IFIT1 RNA-binding channel to enhance specificity for cap 0 RNA over cap 1 or 5'-ppp RNA. Mouse Ifit3 lacks the key C-terminal domain and does not bind mouse Ifit1.","method":"Crystal structure of IFIT1-IFIT3 C-terminal domain complex bound to cap 0 RNA, biochemical binding assays, genetic studies in cells, half-life measurements","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biochemical and genetic validation, multiple orthogonal methods in a single study","pmids":["29525521"],"is_preprint":false},{"year":2018,"finding":"IFIT1 and IFIT3 form a heterodimer via a YxxxL motif present in the C-terminus of each protein. IFIT2/IFIT3 homodimers dissociate to form a more stable IFIT2/IFIT3 heterodimer that associates with IFIT1. IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to cap 0 RNA (Zika virus reporter mRNA), and enhances IFIT1-mediated translation inhibition.","method":"In vitro reconstitution of IFIT complexes, co-IP, motif mutagenesis (YxxxL), cap 0 RNA-binding assays, in vitro translation inhibition assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution with mutagenesis, RNA binding assays, and functional translation assays; independently consistent with PMID 29525521","pmids":["29554348"],"is_preprint":false},{"year":2013,"finding":"Mouse Ifit1 preferentially binds 5' capped 2'O-unmethylated mRNA over 5'-triphosphate RNA and inhibits mRNA translation, thereby restricting replication of a Japanese encephalitis virus 2'O-methyltransferase mutant. Ifit1-deficient macrophages and fibroblasts showed markedly enhanced replication of the JEV MTase mutant.","method":"Ifit1 knockout MEFs and macrophages, viral replication assays, in vitro RNA-binding assays, in vitro translation inhibition assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with defined phenotype, in vitro binding and translation assays, replicated mechanistic finding across multiple labs","pmids":["23824812"],"is_preprint":false},{"year":2016,"finding":"Human IFIT1 and mouse IFIT1 (renamed IFIT1B) are paralogs that diverged >100 million years ago and have distinct antiviral specificities: IFIT1 (human) inhibits viruses encoding a cap 2'O-methyltransferase that IFIT1B cannot inhibit, while IFIT1B selectively inhibits viruses lacking 2'O-methylation. These functional differences were demonstrated using a yeast genetic assay for cap 2'O-methyltransferase suppression and virological assays.","method":"Evolutionary/phylogenetic analysis, yeast genetic complementation assay, virological infection assays comparing IFIT1 and IFIT1B","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (phylogenetics, yeast genetics, virology) in a single rigorous study demonstrating species-specific functional divergence","pmids":["27240734"],"is_preprint":false},{"year":2018,"finding":"IFIT1 functions in the nucleus (in addition to its cytoplasmic role) to negatively regulate the LPS-induced inflammatory gene program and positively regulate type I interferon gene expression in macrophages. These nuclear transcriptional effects are mediated through modulation of a Sin3A-HDAC2 transcriptional regulatory complex at LPS-induced gene loci.","method":"Genome-wide siRNA screen, transcriptional profiling (RNA-seq), chromatin immunoprecipitation showing IFIT1 association with Sin3A-HDAC2 complex at gene loci, subcellular fractionation confirming nuclear IFIT1 localization","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genome-wide screen with follow-up ChIP and transcriptional profiling, single lab, but multiple orthogonal methods","pmids":["30282041"],"is_preprint":false},{"year":2012,"finding":"IFIT1 (ISG56) is primarily responsible for IFN-induced selective inhibition of parainfluenza virus type 5 (PIV5) mRNA translation without causing a general inhibition of cellular protein synthesis. In vitro translation studies confirmed direct inhibition of PIV5 mRNAs by ISG56/IFIT1.","method":"IFN treatment followed by metabolic labeling of viral vs. cellular proteins, IFIT1 knockdown/rescue, in vitro translation assays with purified IFIT1","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro translation with purified protein and knockdown experiments, single lab","pmids":["23052390"],"is_preprint":false},{"year":2016,"finding":"IFIT1 directly inhibits translation of rubulavirus (PIV2, PIV5, mumps) mRNAs but not other paramyxovirus mRNAs. Using purified human IFIT1 and purified mRNA-capping enzymes in an in vitro translation system, efficient inhibition was shown to require a 5' guanosine cap and to be partially abrogated by 2'O methylation of cap 1 ribose. PIV5 M mRNA retained IFIT1 sensitivity even after 2'O methylation, suggesting additional cis-acting structural features influence sensitivity.","method":"In vitro translation with purified human IFIT1, biochemical 2'O methylation of mRNAs with purified capping enzymes, cell-based coinfection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-level in vitro translation with purified components and biochemical modification, single lab but rigorous","pmids":["27512068"],"is_preprint":false},{"year":2015,"finding":"IFIT1 is a major effector of IFN-β antiviral action against alphaviruses, acting to block translation of virion-delivered genomic RNA. IFIT1-independent inhibitory mechanisms also exist. Different alphavirus 5'UTR sequences confer differential sensitivity to IFIT1-mediated translation inhibition. Cell-culture-adaptive mutations in alphavirus 5'UTRs that increase promoter efficiency also decrease resistance to IFIT1.","method":"IFIT1-knockout cells, IFN-β treatment, single-cycle infection assays, 5'UTR chimeric virus constructs, type I IFN induction measurements","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IFIT1 KO cells with defined phenotype and multiple viral constructs with mutant 5'UTRs, single lab","pmids":["25927359"],"is_preprint":false},{"year":2015,"finding":"IFIT1 does not restrict infection by negative-sense RNA viruses (influenza A, La Crosse virus, Oropouche virus, Ebola virus) in cell culture or in Ifit1-/- mice. The binding affinity of IFIT1 for 5'-ppp RNA is approximately 10-fold lower than for cap 0 RNA, explaining the lack of antiviral activity against these viruses whose genomes present 5'-ppp.","method":"Ifit1-/- mouse infection experiments (4 viruses, 3 families), IFIT1 CRISPR-KO A549 cells, ectopic IFIT1 expression in HEK293T, binding affinity measurements for 5'-ppp vs. cap 0 RNA","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — negative finding confirmed across multiple viral families, cell types, and in vivo models with quantitative binding data; this negative result is itself mechanistically informative","pmids":["26157117"],"is_preprint":false},{"year":2015,"finding":"Ifit1 protects against LPS/GalN-induced TNF-α-mediated fatal hepatitis by binding the scaffolding protein Axin and inhibiting its function in mediating JNK activation, thereby suppressing the JNK-Bim apoptotic cascade in hepatocytes.","method":"Co-immunoprecipitation of Ifit1 with Axin, adeno-associated virus-mediated liver-targeted Ifit1 overexpression in mice, JNK phosphorylation assays, apoptosis assays","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP identifying Axin as binding partner with in vivo functional validation in mouse model, single lab","pmids":["26459629"],"is_preprint":false},{"year":2019,"finding":"HEV RNA-dependent RNA polymerase (RdRp) binds to IFIT1 protein, sequestering it and protecting HEV RNA from IFIT1-mediated translation inhibition, thereby enabling successful viral replication despite IFIT1 expression. IFIT1 binds HEV RNA (which has a 5'-cap or 5'-ppp) and inhibits its translation when overexpressed.","method":"Co-immunoprecipitation of HEV RdRp with IFIT1, overexpression/knockdown of IFIT1 in hepatoma cells, viral replication assays, in vitro translation inhibition assays","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with functional rescue assay, single lab","pmids":["30702423"],"is_preprint":false},{"year":2022,"finding":"SARS-CoV-2 NSP16 2'O-methyltransferase activity protects viral RNA from restriction by both IFIT1 and IFIT3. An NSP16 catalytic mutant SARS-CoV-2 showed increased IFN sensitivity, and siRNA knockdown of IFIT1 or IFIT3 partially restored fitness to the NSP16 mutant, demonstrating that both IFIT1 and IFIT3 mediate restriction of unmethylated SARS-CoV-2 RNA.","method":"Engineered SARS-CoV-2 NSP16 active-site mutant, siRNA knockdown of IFIT1/IFIT3, type I IFN sensitivity assays in vitro, hamster in vivo infection model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using siRNA knockdown in the context of recombinant virus with active-site mutation, replicated in two publications (PMIDs 36722972 and 36285486)","pmids":["36722972","36285486"],"is_preprint":false},{"year":2019,"finding":"IFIT1 and IFIT5 binding to capped mRNA is strongly influenced by cap structure modifications. The most stable IFIT1 complexes form with GpppG/A- and m7GpppG/A-capped RNAs (cap 0). NAD+- and NADH-capped RNAs associate with IFIT5 with kinetic parameters comparable to pppG-RNA. Modified synthetic cap analogs incorporated into mRNAs partially protect them from IFIT1-mediated translation inhibition.","method":"Kinetic binding analysis (surface plasmon resonance or equivalent biophysical methods) of IFIT1/IFIT5 interactions with diverse RNA substrates, in vitro translation inhibition assays","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic kinetic binding measurements across multiple RNA substrates plus translation assays, single lab","pmids":["31658992"],"is_preprint":false},{"year":2019,"finding":"Ifit1 does not directly inhibit norovirus translation (which uses a VPg cap substitute that is refractory to Ifit1) but restricts norovirus replication by stimulating interferon-beta expression downstream of cytoplasmic RNA sensing (but not TLR3/TLR4 signaling). Ifit1-KO cells showed enhanced norovirus replication.","method":"CRISPR-Cas9 Ifit1 knockout RAW264.7 cells, virus yield assay, in vitro Ifit1-mediated translation inhibition assay with VPg-linked RNA, qPCR for IFN-β induction after poly(I:C) transfection vs. TLR stimulation","journal":"Wellcome open research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple functional readouts (viral yield, in vitro translation, signaling), single lab","pmids":["31372503"],"is_preprint":false},{"year":2003,"finding":"IFIT1 interacts with Rho/Rac guanine nucleotide exchange factor (GEF) as identified by GST-pulldown from SLE patient white blood cell lysate and MALDI-TOF mass spectrometry.","method":"GST-IFIT1 fusion protein pulldown from patient cell lysate, MALDI-TOF mass spectrometry identification of binding partner","journal":"Rheumatology (Oxford, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown without reciprocal validation or functional follow-up, single lab","pmids":["12777642"],"is_preprint":false},{"year":2025,"finding":"Poxvirus ankyrin protein LSDV012 interacts with IFIT1, alters its subcellular localization, binds its C-terminus, and inhibits its RNA-binding ability without inducing IFIT1 degradation, thereby antagonizing IFIT1-mediated antiviral restriction in a host-species-specific manner.","method":"Co-immunoprecipitation of LSDV012 with IFIT1, subcellular localization imaging, RNA-binding inhibition assays, LSDV012-deletion virus growth assays in IFN-treated cells, phylogenetic analysis","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with localization and functional RNA-binding assays and virus genetic deletion, single lab","pmids":["40096184"],"is_preprint":false},{"year":2025,"finding":"Amino acids 364 and 366 of IFIT1 are sufficient to determine differential anti-VEEV activity between human and chimpanzee IFIT1 (which differ at only 8 positions). Human and bat (black flying fox) IFIT1 strongly bind cap 0 RNA and inhibit VEEV, while chimpanzee IFIT1 does not, despite near-identity. Position 366 is a rapidly evolving residue under positive selection.","method":"Mutagenesis of human IFIT1 (positions 364/366), VEEV infection assays, cap 0 RNA-binding assays across 39 mammalian IFIT1 orthologs, evolutionary analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis combined with functional assays across 39 orthologs, published in peer-reviewed journal, rigorous structure-function analysis","pmids":["41123582"],"is_preprint":false},{"year":2025,"finding":"When IFIT1 is expressed at high levels in the absence of IFIT3, it can inhibit translation of certain 'self' IFN-stimulated gene mRNAs including ISG15 and IFITM1. IFIT1:IFIT3 complex formation rescues ISG15 and IFITM1 from IFIT1-mediated translation inhibition. IFIT1 is degraded by the proteasome in the absence of IFIT3; direct binding to IFIT3 protects IFIT1 from proteasomal degradation, ensuring IFIT1 accumulation only when IFIT3 is co-expressed.","method":"IFIT3-knockout cells, proteasome inhibitor treatment, in vitro translation assays, viral (Semliki Forest virus) infection assays, overexpression experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with multiple functional readouts and proteasome inhibitor rescue, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.11.17.688928"],"is_preprint":true},{"year":2025,"finding":"An MST-based binding assay revealed that the m6Am cap modification (5'-terminal m6A mark in the m7G cap) protects RNA from IFIT1 binding in an additive manner with 2'O-methylation (cap 1). Several noncanonical RNA caps, including trimethylguanosine, unmethylated G-cap, and FAD caps, bind IFIT1 with increased affinity compared to cap 1 RNA. m6A in the 5'UTR (not at the cap-adjacent position) is not recognized by IFIT proteins.","method":"Microscale thermophoresis (MST) binding assay with fluorescently labeled IFIT1 and 13 distinct RNA substrates","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic biophysical binding assay with multiple RNA substrates, single lab, single method","pmids":["39643445"],"is_preprint":false}],"current_model":"IFIT1 is an interferon-stimulated antiviral protein that forms a positively charged RNA-binding tunnel (structurally defined at 1.6 Å) to selectively recognize and bind viral RNAs bearing cap 0 (unmethylated 2'O on first nucleotide) or 5'-triphosphate structures with high affinity, competing with eIF4F (specifically the eIF3 complex) to block translation of foreign mRNAs; IFIT3 binding to IFIT1's C-terminus allosterically enhances cap-0 specificity, stabilizes IFIT1 by protecting it from proteasomal degradation, and prevents IFIT1 from aberrantly targeting self ISG mRNAs; IFIT1 also acts as a negative-feedback regulator of antiviral signaling by binding MITA/STING and disrupting its interactions with VISA and TBK1, and in the nucleus modulates inflammatory vs. interferon gene programs via a Sin3A-HDAC2 complex."},"narrative":{"mechanistic_narrative":"IFIT1 is an interferon-stimulated antiviral effector that discriminates foreign from self mRNA by sensing the chemistry of the 5' cap and the triphosphate terminus, then blocking translation of the bound RNA [PMID:24098121, PMID:23824812]. It binds 5'-triphosphate RNA with nanomolar affinity through an arginine-rich C-terminal groove (R187) [PMID:21642987], but binds cap-0 (2'O-unmethylated) capped RNA roughly an order of magnitude more tightly, making cap-0 recognition its dominant activity [PMID:24098121, PMID:26157117]. A 1.6 Å crystal structure resolves a water-filled, positively charged RNA-binding tunnel whose hydrophobic extension engages the cap in syn and anti conformations; cap-proximal nucleotides supply the affinity needed to outcompete eIF4F, and N1/N2 2'O-methylation sterically interfere with binding, providing the molecular basis for self/nonself discrimination [PMID:28251928]. Sequestration of cap-0 or triphosphate RNA, together with binding to the eIF3e subunit, prevents translation initiation by impairing eIF3-dependent stabilization of the eIF2·GTP·Met-tRNAi ternary complex [PMID:16973618, PMID:24098121]. Through this mechanism IFIT1 restricts viruses that fail to fully cap-methylate their RNA, including coronaviruses, alphaviruses, and rubulaviruses, with antiviral potency tracking the 2'O-methylation status of the viral 5' end [PMID:28251928, PMID:36722972, PMID:36285486, PMID:25927359, PMID:27512068]. IFIT1 specificity and stability are governed by IFIT3: IFIT3 binds the IFIT1 C-terminus via a YxxxL motif, extends IFIT1 half-life by protecting it from proteasomal degradation, and allosterically sharpens IFIT1's preference for cap-0 RNA, preventing aberrant targeting of self ISG mRNAs such as ISG15 and IFITM1 [PMID:29525521, PMID:29554348]. Human IFIT1 and rodent Ifit1 (IFIT1B) are functionally divergent paralogs with distinct cap-methyltransferase specificities, and rapidly evolving residues (e.g., positions 364/366) under positive selection tune antiviral activity across mammals [PMID:27240734, PMID:41123582]. Beyond cap-dependent translational restriction, IFIT1 negatively regulates antiviral signaling by binding MITA/STING and disrupting its association with VISA and TBK1 [PMID:19416887], and acts in the nucleus to modulate inflammatory versus interferon gene programs via a Sin3A-HDAC2 complex [PMID:30282041]. Viruses counter IFIT1 by direct antagonism, including HEV RdRp sequestration and poxvirus ankyrin protein interference with RNA binding [PMID:30702423, PMID:40096184].","teleology":[{"year":2006,"claim":"Established the first molecular mechanism for IFIT1-mediated translational shutdown by identifying eIF3 as a direct target, answering how an ISG could block initiation.","evidence":"Co-IP with eIF3 subunits and in vitro translation inhibition assays","pmids":["16973618"],"confidence":"Medium","gaps":["Did not connect eIF3 binding to RNA-substrate selectivity","Relative contribution of eIF3e binding vs. RNA sequestration to inhibition unresolved"]},{"year":2009,"claim":"Revealed a non-translational role for IFIT1 as a negative-feedback brake on type I IFN signaling, showing it does not only act as an effector but also tunes the response.","evidence":"Reciprocal/competitive co-IP with MITA/STING, IFN-β reporter and VSV rescue assays","pmids":["19416887"],"confidence":"Medium","gaps":["Single lab without structural mapping of the MITA interface","Relationship between this signaling role and cap-binding activity not addressed"]},{"year":2011,"claim":"Defined IFIT1 as a direct PPP-RNA sensor with a specific arginine determinant (R187), establishing the C-terminal charged groove as the RNA-binding site and linking sequestration to viral restriction.","evidence":"Affinity proteomics with PPP-RNA bait, affinity measurements, R187 mutagenesis, Ifit1-KO mouse infection","pmids":["21642987"],"confidence":"High","gaps":["Did not yet establish cap-0 as the preferred ligand","Roles of IFIT2/IFIT3 within the complex not mechanistically dissected"]},{"year":2013,"claim":"Redefined IFIT1's principal ligand as cap-0 (2'O-unmethylated) capped RNA, explaining how it discriminates self (2'O-methylated) from viral mRNA and competes with translation initiation factors.","evidence":"AP-MS, pulsed SILAC-MS, in vitro competition translation assays, and Ifit1-KO cell/virus models (human and mouse)","pmids":["24098121","23824812"],"confidence":"High","gaps":["Structural basis of cap-0 vs. cap-1 discrimination not yet resolved","Species-specific complex composition only partially defined"]},{"year":2016,"claim":"Showed human IFIT1 and mouse Ifit1/IFIT1B are deeply diverged paralogs with distinct cap-methyltransferase specificities, cautioning against direct cross-species mechanistic extrapolation.","evidence":"Phylogenetics, yeast genetic complementation, and comparative virological assays","pmids":["27240734"],"confidence":"High","gaps":["Residue-level determinants of the divergence not pinpointed in this study","Functional consequences for cellular host range incompletely mapped"]},{"year":2017,"claim":"Provided the high-resolution structural mechanism: a positively charged RNA-binding tunnel that engages the cap and uses 2'O-methylation as a steric exclusion signal, defining self/nonself recognition at atomic resolution.","evidence":"1.6 Å crystal structure of RNA-bound IFIT1, gel-shift binding, in vitro translation, structure-guided mutagenesis, coronavirus infection","pmids":["28251928"],"confidence":"High","gaps":["How accessory IFIT proteins reshape the tunnel not addressed","Conformational dynamics in solution inferred indirectly"]},{"year":2018,"claim":"Identified IFIT3 as a regulator that binds the IFIT1 C-terminus via a YxxxL motif, stabilizing IFIT1 and allosterically enhancing its cap-0 specificity, explaining how the complex avoids self-mRNA targeting.","evidence":"Crystal structure of the IFIT1-IFIT3 C-terminal complex on cap-0 RNA, reconstitution, motif mutagenesis, half-life and translation assays","pmids":["29525521","29554348"],"confidence":"High","gaps":["Stoichiometry of higher-order IFIT1/IFIT2/IFIT3 assemblies in cells incompletely defined","Degradation pathway protected by IFIT3 not molecularly identified in these studies"]},{"year":2018,"claim":"Uncovered a distinct nuclear function for IFIT1 in shaping inflammatory vs. interferon gene programs, expanding its role beyond cytoplasmic translation control.","evidence":"Genome-wide siRNA screen, RNA-seq, ChIP showing association with Sin3A-HDAC2, and subcellular fractionation","pmids":["30282041"],"confidence":"Medium","gaps":["Mechanism of IFIT1 nuclear import unknown","Direct vs. indirect recruitment to chromatin not resolved"]},{"year":2015,"claim":"Quantified IFIT1 substrate hierarchy (cap-0 >> 5'-ppp) and mapped its antiviral scope, establishing why negative-sense RNA viruses presenting 5'-ppp escape restriction while 5'UTR features tune sensitivity.","evidence":"Ifit1-KO/CRISPR cells and mice across multiple viral families, 5'UTR chimeras, and binding-affinity measurements","pmids":["26157117","25927359"],"confidence":"High","gaps":["cis-acting 5'UTR determinants of sensitivity not fully defined","IFIT1-independent inhibitory mechanisms remain uncharacterized"]},{"year":2019,"claim":"Systematically mapped how diverse cap chemistries modulate IFIT1 binding, refining the self/nonself code and revealing potential mRNA-therapeutic escape strategies.","evidence":"Kinetic biophysical binding analyses of IFIT1/IFIT5 across diverse RNA caps plus translation assays","pmids":["31658992"],"confidence":"Medium","gaps":["In vivo relevance of noncanonical caps (NAD+/NADH) not established","Single-lab biophysical measurements"]},{"year":2025,"claim":"Extended the cap-recognition code to m6Am and other noncanonical modifications, showing m6Am acts additively with cap-1 2'O-methylation to exclude IFIT1.","evidence":"MST binding assays with 13 RNA substrates","pmids":["39643445"],"confidence":"Medium","gaps":["Single biophysical method without cellular/translation validation for all substrates","Structural basis of m6Am exclusion not determined"]},{"year":2022,"claim":"Demonstrated in pathogen-relevant context that SARS-CoV-2 NSP16 2'O-methylation shields viral RNA from both IFIT1 and IFIT3, validating the self/nonself cap model genetically during a major outbreak.","evidence":"Recombinant NSP16 active-site mutant virus, siRNA knockdown of IFIT1/IFIT3, IFN-sensitivity assays, hamster infection","pmids":["36722972","36285486"],"confidence":"High","gaps":["Did not separate IFIT1 vs. IFIT3 individual contributions cleanly","Knockdown rather than complete knockout"]},{"year":2025,"claim":"Pinpointed rapidly evolving residues (364/366) that determine antiviral activity across mammalian orthologs, providing a molecular handle on positive selection at the IFIT1 host-virus interface.","evidence":"Mutagenesis of human IFIT1, VEEV infection and cap-0 binding assays across 39 orthologs, evolutionary analysis","pmids":["41123582"],"confidence":"High","gaps":["Structural mechanism by which position 366 alters function not solved","Generalizability beyond VEEV/alphaviruses untested"]},{"year":2025,"claim":"Showed that uncomplexed IFIT1 can aberrantly inhibit self ISG mRNAs and is proteasomally degraded, while IFIT3 binding both stabilizes IFIT1 and prevents self-targeting, integrating stability and specificity control.","evidence":"IFIT3-KO cells, proteasome inhibition, in vitro translation, and SFV infection (preprint)","pmids":["bio_10.1101_2025.11.17.688928"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","E3 ligase/degron mediating IFIT1 turnover not identified"]},{"year":2025,"claim":"Defined a viral antagonism mechanism in which poxvirus ankyrin protein LSDV012 binds the IFIT1 C-terminus and blocks RNA binding without triggering degradation, illustrating direct effector neutralization.","evidence":"Co-IP, localization imaging, RNA-binding inhibition assays, and LSDV012-deletion virus growth in IFN-treated cells","pmids":["40096184"],"confidence":"Medium","gaps":["Structural details of the LSDV012-IFIT1 interface unresolved","Single lab"]},{"year":null,"claim":"How IFIT1's distinct activities — cytoplasmic cap-dependent translation inhibition, STING-mediated signaling feedback, and nuclear Sin3A-HDAC2 transcriptional modulation — are coordinated within a cell and what governs IFIT1 nuclear import remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Mechanism of IFIT1 nuclear localization unknown","No integrated model linking RNA-binding and signaling/transcriptional roles","E3 ligase governing IFIT1 turnover unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,4,7,17,23]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[1,3,10,11]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,7]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,16,15,20]}],"complexes":["IFIT1-IFIT3 heterodimer","IFIT1/IFIT2/IFIT3 complex","Sin3A-HDAC2 complex (nuclear)"],"partners":["IFIT3","IFIT2","EIF3E","STING1","TBK1","AXIN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09914","full_name":"Antiviral innate immune response effector IFIT1","aliases":["Interferon-induced 56 kDa protein","IFI-56K","P56","Interferon-induced protein with tetratricopeptide repeats 1"],"length_aa":478,"mass_kda":55.4,"function":"Plays a key role in the innate immune response as part of an interferon-dependent multiprotein complex, recognizing and sequestering viral RNAs that lack host-specific 2'-O-methylation at their 5' cap. By distinguishing these RNAs from host mRNAs, inhibits their translation by competing with the translation initiation factor eIF4E (PubMed:21642987, PubMed:27240734, PubMed:39009378, PubMed:23334420, PubMed:28251928, PubMed:36285486). Could also prevent viral replication through its interaction with DNA replication origin-binding protein E1 of several viruses. Causes the translocation of E1 from the nucleus to the cytoplasm and can also inhibit its helicase activity in vitro (PubMed:19008854, PubMed:21976647). Exhibits antiviral activity against many viruses from the Flaviviridae (West Nile virus, Dengue virus, hepatitis C virus), Coronaviridae (human 229E coronavirus, SARS-CoV-2 and SARS-CoV), Poxviridae (vaccinia virus) and Togaviridae (Sindbis virus) families (PubMed:19008854, PubMed:21976647, PubMed:28251928, PubMed:36285486)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P09914/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFIT1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFIT1","total_profiled":1310},"omim":[{"mim_id":"618886","title":"PSEUDO-TORCH SYNDROME 3; PTORCH3","url":"https://www.omim.org/entry/618886"},{"mim_id":"616135","title":"INTERFERON-INDUCED PROTEIN WITH TETRATRICOPEPTIDE REPEATS 5; IFIT5","url":"https://www.omim.org/entry/616135"},{"mim_id":"606609","title":"3-PRIME @REPAIR EXONUCLEASE 1; TREX1","url":"https://www.omim.org/entry/606609"},{"mim_id":"225750","title":"AICARDI-GOUTIERES SYNDROME 1; AGS1","url":"https://www.omim.org/entry/225750"},{"mim_id":"147690","title":"INTERFERON-INDUCED PROTEIN WITH TETRATRICOPEPTIDE REPEATS 1; IFIT1","url":"https://www.omim.org/entry/147690"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFIT1"},"hgnc":{"alias_symbol":["GARG-16","ISG56"],"prev_symbol":["G10P1","IFI56","IFNAI1"]},"alphafold":{"accession":"P09914","domains":[{"cath_id":"1.25.40.10","chopping":"3-137","consensus_level":"high","plddt":91.6221,"start":3,"end":137}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09914","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09914-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09914-F1-predicted_aligned_error_v6.png","plddt_mean":94.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFIT1","jax_strain_url":"https://www.jax.org/strain/search?query=IFIT1"},"sequence":{"accession":"P09914","fasta_url":"https://rest.uniprot.org/uniprotkb/P09914.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09914/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09914"}},"corpus_meta":[{"pmid":"21642987","id":"PMC_21642987","title":"IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21642987","citation_count":410,"is_preprint":false},{"pmid":"20950130","id":"PMC_20950130","title":"The ISG56/IFIT1 gene family.","date":"2010","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/20950130","citation_count":246,"is_preprint":false},{"pmid":"24098121","id":"PMC_24098121","title":"Sequestration by IFIT1 impairs translation of 2'O-unmethylated capped RNA.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24098121","citation_count":179,"is_preprint":false},{"pmid":"19416887","id":"PMC_19416887","title":"ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19416887","citation_count":176,"is_preprint":false},{"pmid":"22589727","id":"PMC_22589727","title":"2'-O methylation of the viral mRNA cap by West Nile virus evades ifit1-dependent and -independent mechanisms of host restriction in vivo.","date":"2012","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/22589727","citation_count":144,"is_preprint":false},{"pmid":"16973618","id":"PMC_16973618","title":"Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16973618","citation_count":139,"is_preprint":false},{"pmid":"21976647","id":"PMC_21976647","title":"ISG56 and IFITM1 proteins inhibit hepatitis C virus replication.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21976647","citation_count":129,"is_preprint":false},{"pmid":"17079283","id":"PMC_17079283","title":"Coordinated regulation and widespread cellular expression of interferon-stimulated genes (ISG) ISG-49, ISG-54, and ISG-56 in the central nervous system after infection with distinct viruses.","date":"2006","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17079283","citation_count":113,"is_preprint":false},{"pmid":"33707417","id":"PMC_33707417","title":"Cancer-associated fibroblast-derived CXCL11 modulates hepatocellular carcinoma cell migration and tumor metastasis through the circUBAP2/miR-4756/IFIT1/3 axis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33707417","citation_count":110,"is_preprint":false},{"pmid":"29525521","id":"PMC_29525521","title":"Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability.","date":"2018","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29525521","citation_count":106,"is_preprint":false},{"pmid":"28251928","id":"PMC_28251928","title":"Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28251928","citation_count":103,"is_preprint":false},{"pmid":"23824812","id":"PMC_23824812","title":"Ifit1 inhibits Japanese encephalitis virus replication through binding to 5' capped 2'-O unmethylated RNA.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23824812","citation_count":99,"is_preprint":false},{"pmid":"24909568","id":"PMC_24909568","title":"IFIT1: A dual sensor and effector molecule that detects non-2'-O methylated viral RNA and inhibits its translation.","date":"2014","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24909568","citation_count":93,"is_preprint":false},{"pmid":"25927359","id":"PMC_25927359","title":"IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon.","date":"2015","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25927359","citation_count":92,"is_preprint":false},{"pmid":"29554348","id":"PMC_29554348","title":"IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29554348","citation_count":90,"is_preprint":false},{"pmid":"30626937","id":"PMC_30626937","title":"IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30626937","citation_count":84,"is_preprint":false},{"pmid":"30282041","id":"PMC_30282041","title":"IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30282041","citation_count":84,"is_preprint":false},{"pmid":"27240734","id":"PMC_27240734","title":"Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27240734","citation_count":81,"is_preprint":false},{"pmid":"12777642","id":"PMC_12777642","title":"Protein interaction for an interferon-inducible systemic lupus associated gene, IFIT1.","date":"2003","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12777642","citation_count":62,"is_preprint":false},{"pmid":"8660659","id":"PMC_8660659","title":"The glucocorticoid attenuated response genes GARG-16, GARG-39, and GARG-49/IRG2 encode inducible proteins containing multiple tetratricopeptide repeat domains.","date":"1996","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/8660659","citation_count":57,"is_preprint":false},{"pmid":"17553874","id":"PMC_17553874","title":"Tissue-specific and inducer-specific differential induction of ISG56 and ISG54 in mice.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17553874","citation_count":56,"is_preprint":false},{"pmid":"36371909","id":"PMC_36371909","title":"Fusobacterium nucleatum stimulates cell proliferation and promotes PD-L1 expression via IFIT1-related signal in colorectal cancer.","date":"2022","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36371909","citation_count":53,"is_preprint":false},{"pmid":"7896268","id":"PMC_7896268","title":"Structure, chromosome localization, and regulation of expression of the interferon-regulated mouse Ifi54/Ifi56 gene family.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7896268","citation_count":51,"is_preprint":false},{"pmid":"36285486","id":"PMC_36285486","title":"Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/36285486","citation_count":43,"is_preprint":false},{"pmid":"26157117","id":"PMC_26157117","title":"Human and Murine IFIT1 Proteins Do Not Restrict Infection of Negative-Sense RNA Viruses of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26157117","citation_count":42,"is_preprint":false},{"pmid":"32541772","id":"PMC_32541772","title":"Annexin-A1 promotes RIG-I-dependent signaling and apoptosis via regulation of the IRF3-IFNAR-STAT1-IFIT1 pathway in A549 lung epithelial cells.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32541772","citation_count":41,"is_preprint":false},{"pmid":"36722972","id":"PMC_36722972","title":"SARS-CoV-2 Uses Nonstructural Protein 16 To Evade Restriction by IFIT1 and IFIT3.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/36722972","citation_count":39,"is_preprint":false},{"pmid":"23052390","id":"PMC_23052390","title":"ISG56/IFIT1 is primarily responsible for interferon-induced changes to patterns of parainfluenza virus type 5 transcription and protein synthesis.","date":"2012","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/23052390","citation_count":39,"is_preprint":false},{"pmid":"32499867","id":"PMC_32499867","title":"Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway.","date":"2020","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/32499867","citation_count":34,"is_preprint":false},{"pmid":"36138395","id":"PMC_36138395","title":"circ_0086296 induced atherosclerotic lesions via the IFIT1/STAT1 feedback loop by sponging miR-576-3p.","date":"2022","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/36138395","citation_count":33,"is_preprint":false},{"pmid":"27512068","id":"PMC_27512068","title":"Human IFIT1 Inhibits mRNA Translation of Rubulaviruses but Not Other Members of the Paramyxoviridae Family.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/27512068","citation_count":33,"is_preprint":false},{"pmid":"23785202","id":"PMC_23785202","title":"MicroRNA profiling of Sendai virus-infected A549 cells identifies miR-203 as an interferon-inducible regulator of IFIT1/ISG56.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23785202","citation_count":32,"is_preprint":false},{"pmid":"22745654","id":"PMC_22745654","title":"Identification and validation of Ifit1 as an important innate immune bottleneck.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22745654","citation_count":30,"is_preprint":false},{"pmid":"24630834","id":"PMC_24630834","title":"ISG54 and ISG56 are induced by TLR3 signaling in U373MG human astrocytoma cells: possible involvement in CXCL10 expression.","date":"2014","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/24630834","citation_count":25,"is_preprint":false},{"pmid":"26423178","id":"PMC_26423178","title":"Interferon-stimulated gene (ISG) 60, as well as ISG56 and ISG54, positively regulates TLR3/IFN-β/STAT1 axis in U373MG human astrocytoma cells.","date":"2015","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/26423178","citation_count":24,"is_preprint":false},{"pmid":"23684765","id":"PMC_23684765","title":"MDA5 and ISG56 mediate CXCL10 expression induced by toll-like receptor 4 activation in U373MG human astrocytoma cells.","date":"2013","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/23684765","citation_count":22,"is_preprint":false},{"pmid":"34791638","id":"PMC_34791638","title":"IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/β-catenin signaling.","date":"2021","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/34791638","citation_count":21,"is_preprint":false},{"pmid":"30702423","id":"PMC_30702423","title":"Hepatitis E virus polymerase binds to IFIT1 to protect the viral RNA from IFIT1-mediated translation inhibition.","date":"2019","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/30702423","citation_count":18,"is_preprint":false},{"pmid":"35280763","id":"PMC_35280763","title":"COL8A1 Promotes NSCLC Progression Through IFIT1/IFIT3-Mediated EGFR Activation.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35280763","citation_count":18,"is_preprint":false},{"pmid":"31658992","id":"PMC_31658992","title":"Kinetic analysis of IFIT1 and IFIT5 interactions with different native and engineered RNAs and its consequences for designing mRNA-based therapeutics.","date":"2019","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31658992","citation_count":18,"is_preprint":false},{"pmid":"27589693","id":"PMC_27589693","title":"Antiviral effects of IFIT1 in human cytomegalovirus-infected fetal astrocytes.","date":"2016","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/27589693","citation_count":18,"is_preprint":false},{"pmid":"26459629","id":"PMC_26459629","title":"Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway.","date":"2015","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26459629","citation_count":17,"is_preprint":false},{"pmid":"29562196","id":"PMC_29562196","title":"A Talented Duo: IFIT1 and IFIT3 Patrol Viral RNA Caps.","date":"2018","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29562196","citation_count":17,"is_preprint":false},{"pmid":"28869524","id":"PMC_28869524","title":"HPV16 E6 and E7 Upregulate Interferon-Induced Antiviral Response Genes ISG15 and IFIT1 in Human Trophoblast Cells.","date":"2017","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/28869524","citation_count":15,"is_preprint":false},{"pmid":"29629559","id":"PMC_29629559","title":"IFIT1 Expression Patterns Induced by H9N2 Virus and Inactivated Viral Particle in Human Umbilical Vein Endothelial Cells and Bronchus Epithelial Cells.","date":"2018","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/29629559","citation_count":14,"is_preprint":false},{"pmid":"31372503","id":"PMC_31372503","title":"Ifit1 regulates norovirus infection and enhances the interferon response in murine macrophage-like cells.","date":"2019","source":"Wellcome open research","url":"https://pubmed.ncbi.nlm.nih.gov/31372503","citation_count":14,"is_preprint":false},{"pmid":"11398178","id":"PMC_11398178","title":"Lipopolysaccharide-induced switch between retinoid receptor (RXR) alpha and glucocorticoid attenuated response gene (GARG)-16 messenger RNAs in cultured rat microglia.","date":"2001","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/11398178","citation_count":13,"is_preprint":false},{"pmid":"38462032","id":"PMC_38462032","title":"Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38462032","citation_count":12,"is_preprint":false},{"pmid":"38898490","id":"PMC_38898490","title":"IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC).","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38898490","citation_count":12,"is_preprint":false},{"pmid":"32551893","id":"PMC_32551893","title":"Lipopolysaccharide Promotes Inflammatory Response via Enhancing IFIT1 Expression in Human Umbilical Vein Endothelial Cells.","date":"2020","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32551893","citation_count":12,"is_preprint":false},{"pmid":"40096184","id":"PMC_40096184","title":"A poxvirus ankyrin protein LSDV012 inhibits IFIT1 in a host-species-specific manner by compromising its RNA binding ability.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/40096184","citation_count":11,"is_preprint":false},{"pmid":"20411041","id":"PMC_20411041","title":"Common Variation in the CYP17A1 and IFIT1 Genes on Chromosome 10 Does Not Contribute to the Risk of Endometriosis.","date":"2008","source":"The open reproductive science journal","url":"https://pubmed.ncbi.nlm.nih.gov/20411041","citation_count":11,"is_preprint":false},{"pmid":"36298646","id":"PMC_36298646","title":"Simultaneous Detection of RIG-1, MDA5, and IFIT-1 Expression Is a Convenient Tool for Evaluation of the Interferon-Mediated Response.","date":"2022","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/36298646","citation_count":10,"is_preprint":false},{"pmid":"38901242","id":"PMC_38901242","title":"Single-cell transcriptomics of blood identified IFIT1+ neutrophil subcluster expansion in NTM-PD patients.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38901242","citation_count":9,"is_preprint":false},{"pmid":"38536650","id":"PMC_38536650","title":"IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/β-catenin signaling.","date":"2024","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/38536650","citation_count":9,"is_preprint":false},{"pmid":"37496288","id":"PMC_37496288","title":"Lysyl oxidase-like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/37496288","citation_count":9,"is_preprint":false},{"pmid":"27823966","id":"PMC_27823966","title":"The association between expression of IFIT1 in podocytes of MRL/lpr mice and the renal pathological changes it causes: An animal study.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27823966","citation_count":9,"is_preprint":false},{"pmid":"28499966","id":"PMC_28499966","title":"Interferon-induced protein 56 (IFI56) is induced by VHSV infection but not by bacterial infection in olive flounder (Paralichthys olivaceus).","date":"2017","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28499966","citation_count":9,"is_preprint":false},{"pmid":"35034537","id":"PMC_35034537","title":"Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) accelerates osteoclast formation by regulating signal transducer and activator of transcription 3 (STAT3) signalling.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35034537","citation_count":9,"is_preprint":false},{"pmid":"27956805","id":"PMC_27956805","title":"IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection.","date":"2016","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/27956805","citation_count":9,"is_preprint":false},{"pmid":"32363951","id":"PMC_32363951","title":"ISG56 is involved in CXCL10 expression induced by TLR3 signaling in BEAS-2B bronchial epithelial cells.","date":"2020","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/32363951","citation_count":8,"is_preprint":false},{"pmid":"31476389","id":"PMC_31476389","title":"Grouper IFIT1 inhibits iridovirus and nodavirus infection by positively regulating interferon response.","date":"2019","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31476389","citation_count":8,"is_preprint":false},{"pmid":"36446235","id":"PMC_36446235","title":"Overexpression of IFIT1 protects against LPS-induced acute lung injury via regulating CCL5-p65NF-κB signaling.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36446235","citation_count":8,"is_preprint":false},{"pmid":"37817224","id":"PMC_37817224","title":"Kruppel-like factor 13 acts as a tumor suppressor in thyroid carcinoma by downregulating IFIT1.","date":"2023","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/37817224","citation_count":7,"is_preprint":false},{"pmid":"35038119","id":"PMC_35038119","title":"The Highly Expressed IFIT1 in Nasopharyngeal Carcinoma Enhances Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma Cells.","date":"2022","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35038119","citation_count":6,"is_preprint":false},{"pmid":"41123582","id":"PMC_41123582","title":"IFIT1 is rapidly evolving and exhibits disparate antiviral activities across 11 mammalian orders.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/41123582","citation_count":4,"is_preprint":false},{"pmid":"24630528","id":"PMC_24630528","title":"Loop de loop: viral RNA evades IFIT1 targeting.","date":"2014","source":"Trends in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24630528","citation_count":4,"is_preprint":false},{"pmid":"40146622","id":"PMC_40146622","title":"The Cap-proximal secondary structures of the 5'UTRs of parainfluenza virus 5 mRNAs specify differential sensitivity to type I interferon and IFIT1.","date":"2025","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/40146622","citation_count":4,"is_preprint":false},{"pmid":"39748231","id":"PMC_39748231","title":"Downregulation of PAX1 in OSCC Enhances Stemness and Immunosuppression via IFIT1 and PD-L1 Pathways.","date":"2025","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39748231","citation_count":3,"is_preprint":false},{"pmid":"38483660","id":"PMC_38483660","title":"TMEM2 suppresses TLR3-mediated IFN-β/ISG56/CXCL10 expression in BEAS-2B bronchial epithelial cells.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38483660","citation_count":3,"is_preprint":false},{"pmid":"35027832","id":"PMC_35027832","title":"Bioinformation Analysis Reveals IFIT1 as Potential Biomarkers in Central Nervous System Tuberculosis.","date":"2022","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/35027832","citation_count":3,"is_preprint":false},{"pmid":"38798375","id":"PMC_38798375","title":"IFIT1 is rapidly evolving and exhibits disparate antiviral activities across 11 mammalian orders.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38798375","citation_count":3,"is_preprint":false},{"pmid":"12899756","id":"PMC_12899756","title":"[Using GST-tag to capture protein interaction of an interferon-inducible systemic lupus associated gene, IFIT1].","date":"2003","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/12899756","citation_count":2,"is_preprint":false},{"pmid":"36203546","id":"PMC_36203546","title":"SARS-CoV-2 Uses Nonstructural Protein 16 to Evade Restriction by IFIT1 and IFIT3.","date":"2022","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36203546","citation_count":1,"is_preprint":false},{"pmid":"39643445","id":"PMC_39643445","title":"An MST-based assay reveals new binding preferences of IFIT1 for canonically and noncanonically capped RNAs.","date":"2025","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39643445","citation_count":1,"is_preprint":false},{"pmid":"31502557","id":"PMC_31502557","title":"In silico structure analysis of alphaviral RNA genomes shows diversity in the evasion of IFIT1-mediated innate immunity.","date":"2019","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/31502557","citation_count":1,"is_preprint":false},{"pmid":"41911548","id":"PMC_41911548","title":"Pathogenic Ifit1 + neutrophils driven by IRF7 promote liver injury and represent a therapeutic target in acute liver failure.","date":"2026","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/41911548","citation_count":1,"is_preprint":false},{"pmid":"21129252","id":"PMC_21129252","title":"[Expression of ifi56 gene in ATRA-induced APL cell differentiation and construction of ifi56 gene eukaryotic expression plasmid].","date":"2010","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/21129252","citation_count":0,"is_preprint":false},{"pmid":"41267985","id":"PMC_41267985","title":"Transcriptomic analysis reveals TME-mediated macrophage IFIT1 upregulation and CX3CR1 suppression drive osteosarcoma progression.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41267985","citation_count":0,"is_preprint":false},{"pmid":"41479373","id":"PMC_41479373","title":"1,3,6-Tri-O-Galloyl-β-D-Glucose Alleviates Sepsis-Induced Lung Damage by Inhibiting Inflammatory Response and Oxidative Stress Through Targeting Neutrophil IFIT1.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41479373","citation_count":0,"is_preprint":false},{"pmid":"42185863","id":"PMC_42185863","title":"Arecoline-induced EV-mediated ZNF582 hypermethylation drives IFIT1-PD-L1 immune evasion in oral squamous cell carcinoma.","date":"2026","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/42185863","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.17.688928","title":"IFIT3 controls IFIT1 accumulation and specificity preventing self mRNA targeting during the innate immune response","date":"2025-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.17.688928","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.17.599308","title":"VPS34-IN1 inhibits cap-mediated translation and synergizes with STING to drive type-I IFN expression in human plasmacytoid DCs","date":"2024-06-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.17.599308","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.28.679079","title":"NK cell allorecognition shapes reprogramming of neutrophils infiltrating heart allografts","date":"2025-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.28.679079","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.18.670784","title":"<i>VILMIR</i>  is a  <i>trans</i>  -acting long noncoding RNA that enhances the host interferon response in human epithelial cells","date":"2025-08-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670784","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.16.662511","title":"Fatty Acid Synthase associates with nuclear-derived cytoplasmic dsRNA molecules and influences antiviral innate immune response","date":"2025-07-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.16.662511","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.09.663835","title":"Granulin  <sup>+</sup>  macrophages promote lineage plasticity in prostate cancer through paracrine signaling loops","date":"2025-07-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.09.663835","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.17.665358","title":"N-acetyltransferase 10 promotes mRNA stability of immune response factors to modulate Zika virus infection","date":"2025-07-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.17.665358","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.05.658176","title":"Regulators of Interferon-Responsive Microglia Uncovered by Genome-wide CRISPRi Screening","date":"2025-06-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.05.658176","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.18.649619","title":"Predicting Early Transitions in Respiratory Virus Infections via Critical Transient Gene Interactions","date":"2025-04-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.18.649619","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.25.600627","title":"Cap-related modifications of RNA regulate binding to IFIT proteins","date":"2024-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.25.600627","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.18.619140","title":"The Role of ISG15 in Cancer Biology: Systematic Evaluation of ISG15 Expression and Its Molecular Interactions in a Pan-Cancer Context","date":"2024-10-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.18.619140","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.18.604120","title":"The cGAS-STING Pathway Is Essential in Acute Ischemia-Induced Neutropoiesis and Neutrophil Priming in the Bone Marrow","date":"2024-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.18.604120","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.23.604777","title":"SARS-CoV-2 S, M and E Structural Proteins Down-modulate HIV-1 LTR Activity and Modulate Endoplasmic Reticulum Stress Responses","date":"2024-07-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.23.604777","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.02.601267","title":"Molecular characterization of response to etrolizumab and anti-TNF reveals treatment resistance in ulcerative colitis is associated with an abundance of residual neutrophil subsets and inflammatory fibroblast populations","date":"2024-07-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.02.601267","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52624,"output_tokens":6637,"usd":0.128714,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15551,"output_tokens":5239,"usd":0.104365,"stage2_stop_reason":"end_turn"},"total_usd":0.233079,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"IFIT1 directly binds 5'-triphosphate RNA (PPP-RNA) with nanomolar affinity, requiring arginine at position 187 in a highly charged carboxy-terminal groove. It mediates assembly of a larger protein complex containing other IFIT family members (IFIT2, IFIT3) that sequesters viral PPP-RNA, restricting viral replication.\",\n      \"method\": \"Affinity proteomics with PPP-RNA bait, binding affinity measurements, site-directed mutagenesis (R187), Ifit1-knockout mouse infection experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding assay with mutagenesis, affinity measurements, and in vivo KO validation across multiple viral pathogens, replicated in subsequent studies\",\n      \"pmids\": [\"21642987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFIT1 is the sole interferon-induced protein that selectively binds 2'O-unmethylated capped RNA (cap 0) over 2'O-methylated capped RNA (cap 1). IFIT1 tethers a species-specific complex of other IFIT proteins to RNA and sequesters cap-0 RNA, thereby competitively impairing binding of eukaryotic translation initiation factors to the RNA template and inhibiting translation.\",\n      \"method\": \"Proteome-wide affinity purification coupled to mass spectrometry, pulsed SILAC-MS, in vitro competition translation assays, functional validation with viral infection models\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (AP-MS, SILAC, in vitro competition), independently replicated across multiple studies\",\n      \"pmids\": [\"24098121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IFIT1 (ISG56) binds the adapter protein MITA (also known as STING) and disrupts interactions between MITA and the upstream signaling components VISA and TBK1, thereby inhibiting virus-triggered IRF3/NF-κB activation and type I IFN production — functioning as a negative-feedback regulator.\",\n      \"method\": \"Co-immunoprecipitation, competitive co-IP, overexpression/knockdown experiments, IFN-β promoter reporter assay, VSV replication rescue assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal co-IP and competitive co-IP with functional readout (IFN-β induction, viral replication), single lab\",\n      \"pmids\": [\"19416887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IFIT1 (P56) and its paralog IFIT2 (P54) bind to the translation initiation factor eIF3 and inhibit translation; IFIT1 specifically binds the 'e' subunit of eIF3 and inhibits the ability of eIF3 to stabilize the eIF2·GTP·Met-tRNAi ternary complex.\",\n      \"method\": \"Co-immunoprecipitation with eIF3 subunits, in vitro translation inhibition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with eIF3 subunits plus functional in vitro translation assay, single lab\",\n      \"pmids\": [\"16973618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of RNA-bound human IFIT1 (1.6 Å with capped RNA) reveals a water-filled, positively charged RNA-binding tunnel with a hydrophobic extension that engages the mRNA cap in multiple conformations (syn and anti). Cap-proximal nucleotides provide affinity to compete with eIF4F. N1 2'O-methylation and N2 2'O-methylation both interfere with IFIT1 binding, revealing synergistic roles for these modifications in self- vs. nonself-mRNA discrimination. Mutagenesis confirmed RNA binding is required for antiviral restriction of a coronavirus lacking N1 methylation.\",\n      \"method\": \"X-ray crystallography, gel-shift binding assays, in vitro translation assays, structure-guided mutagenesis, coronavirus infection experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional validation by mutagenesis and binding assays in a single rigorous study\",\n      \"pmids\": [\"28251928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human IFIT3 binds to IFIT1 via its C-terminal domain and has dual regulatory functions: (1) it extends the half-life of IFIT1, increasing its steady-state abundance; and (2) it allosterically modulates the IFIT1 RNA-binding channel to enhance specificity for cap 0 RNA over cap 1 or 5'-ppp RNA. Mouse Ifit3 lacks the key C-terminal domain and does not bind mouse Ifit1.\",\n      \"method\": \"Crystal structure of IFIT1-IFIT3 C-terminal domain complex bound to cap 0 RNA, biochemical binding assays, genetic studies in cells, half-life measurements\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biochemical and genetic validation, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"29525521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFIT1 and IFIT3 form a heterodimer via a YxxxL motif present in the C-terminus of each protein. IFIT2/IFIT3 homodimers dissociate to form a more stable IFIT2/IFIT3 heterodimer that associates with IFIT1. IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to cap 0 RNA (Zika virus reporter mRNA), and enhances IFIT1-mediated translation inhibition.\",\n      \"method\": \"In vitro reconstitution of IFIT complexes, co-IP, motif mutagenesis (YxxxL), cap 0 RNA-binding assays, in vitro translation inhibition assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution with mutagenesis, RNA binding assays, and functional translation assays; independently consistent with PMID 29525521\",\n      \"pmids\": [\"29554348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mouse Ifit1 preferentially binds 5' capped 2'O-unmethylated mRNA over 5'-triphosphate RNA and inhibits mRNA translation, thereby restricting replication of a Japanese encephalitis virus 2'O-methyltransferase mutant. Ifit1-deficient macrophages and fibroblasts showed markedly enhanced replication of the JEV MTase mutant.\",\n      \"method\": \"Ifit1 knockout MEFs and macrophages, viral replication assays, in vitro RNA-binding assays, in vitro translation inhibition assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with defined phenotype, in vitro binding and translation assays, replicated mechanistic finding across multiple labs\",\n      \"pmids\": [\"23824812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human IFIT1 and mouse IFIT1 (renamed IFIT1B) are paralogs that diverged >100 million years ago and have distinct antiviral specificities: IFIT1 (human) inhibits viruses encoding a cap 2'O-methyltransferase that IFIT1B cannot inhibit, while IFIT1B selectively inhibits viruses lacking 2'O-methylation. These functional differences were demonstrated using a yeast genetic assay for cap 2'O-methyltransferase suppression and virological assays.\",\n      \"method\": \"Evolutionary/phylogenetic analysis, yeast genetic complementation assay, virological infection assays comparing IFIT1 and IFIT1B\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (phylogenetics, yeast genetics, virology) in a single rigorous study demonstrating species-specific functional divergence\",\n      \"pmids\": [\"27240734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFIT1 functions in the nucleus (in addition to its cytoplasmic role) to negatively regulate the LPS-induced inflammatory gene program and positively regulate type I interferon gene expression in macrophages. These nuclear transcriptional effects are mediated through modulation of a Sin3A-HDAC2 transcriptional regulatory complex at LPS-induced gene loci.\",\n      \"method\": \"Genome-wide siRNA screen, transcriptional profiling (RNA-seq), chromatin immunoprecipitation showing IFIT1 association with Sin3A-HDAC2 complex at gene loci, subcellular fractionation confirming nuclear IFIT1 localization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genome-wide screen with follow-up ChIP and transcriptional profiling, single lab, but multiple orthogonal methods\",\n      \"pmids\": [\"30282041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IFIT1 (ISG56) is primarily responsible for IFN-induced selective inhibition of parainfluenza virus type 5 (PIV5) mRNA translation without causing a general inhibition of cellular protein synthesis. In vitro translation studies confirmed direct inhibition of PIV5 mRNAs by ISG56/IFIT1.\",\n      \"method\": \"IFN treatment followed by metabolic labeling of viral vs. cellular proteins, IFIT1 knockdown/rescue, in vitro translation assays with purified IFIT1\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro translation with purified protein and knockdown experiments, single lab\",\n      \"pmids\": [\"23052390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IFIT1 directly inhibits translation of rubulavirus (PIV2, PIV5, mumps) mRNAs but not other paramyxovirus mRNAs. Using purified human IFIT1 and purified mRNA-capping enzymes in an in vitro translation system, efficient inhibition was shown to require a 5' guanosine cap and to be partially abrogated by 2'O methylation of cap 1 ribose. PIV5 M mRNA retained IFIT1 sensitivity even after 2'O methylation, suggesting additional cis-acting structural features influence sensitivity.\",\n      \"method\": \"In vitro translation with purified human IFIT1, biochemical 2'O methylation of mRNAs with purified capping enzymes, cell-based coinfection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-level in vitro translation with purified components and biochemical modification, single lab but rigorous\",\n      \"pmids\": [\"27512068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFIT1 is a major effector of IFN-β antiviral action against alphaviruses, acting to block translation of virion-delivered genomic RNA. IFIT1-independent inhibitory mechanisms also exist. Different alphavirus 5'UTR sequences confer differential sensitivity to IFIT1-mediated translation inhibition. Cell-culture-adaptive mutations in alphavirus 5'UTRs that increase promoter efficiency also decrease resistance to IFIT1.\",\n      \"method\": \"IFIT1-knockout cells, IFN-β treatment, single-cycle infection assays, 5'UTR chimeric virus constructs, type I IFN induction measurements\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IFIT1 KO cells with defined phenotype and multiple viral constructs with mutant 5'UTRs, single lab\",\n      \"pmids\": [\"25927359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFIT1 does not restrict infection by negative-sense RNA viruses (influenza A, La Crosse virus, Oropouche virus, Ebola virus) in cell culture or in Ifit1-/- mice. The binding affinity of IFIT1 for 5'-ppp RNA is approximately 10-fold lower than for cap 0 RNA, explaining the lack of antiviral activity against these viruses whose genomes present 5'-ppp.\",\n      \"method\": \"Ifit1-/- mouse infection experiments (4 viruses, 3 families), IFIT1 CRISPR-KO A549 cells, ectopic IFIT1 expression in HEK293T, binding affinity measurements for 5'-ppp vs. cap 0 RNA\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — negative finding confirmed across multiple viral families, cell types, and in vivo models with quantitative binding data; this negative result is itself mechanistically informative\",\n      \"pmids\": [\"26157117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ifit1 protects against LPS/GalN-induced TNF-α-mediated fatal hepatitis by binding the scaffolding protein Axin and inhibiting its function in mediating JNK activation, thereby suppressing the JNK-Bim apoptotic cascade in hepatocytes.\",\n      \"method\": \"Co-immunoprecipitation of Ifit1 with Axin, adeno-associated virus-mediated liver-targeted Ifit1 overexpression in mice, JNK phosphorylation assays, apoptosis assays\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP identifying Axin as binding partner with in vivo functional validation in mouse model, single lab\",\n      \"pmids\": [\"26459629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HEV RNA-dependent RNA polymerase (RdRp) binds to IFIT1 protein, sequestering it and protecting HEV RNA from IFIT1-mediated translation inhibition, thereby enabling successful viral replication despite IFIT1 expression. IFIT1 binds HEV RNA (which has a 5'-cap or 5'-ppp) and inhibits its translation when overexpressed.\",\n      \"method\": \"Co-immunoprecipitation of HEV RdRp with IFIT1, overexpression/knockdown of IFIT1 in hepatoma cells, viral replication assays, in vitro translation inhibition assays\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with functional rescue assay, single lab\",\n      \"pmids\": [\"30702423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SARS-CoV-2 NSP16 2'O-methyltransferase activity protects viral RNA from restriction by both IFIT1 and IFIT3. An NSP16 catalytic mutant SARS-CoV-2 showed increased IFN sensitivity, and siRNA knockdown of IFIT1 or IFIT3 partially restored fitness to the NSP16 mutant, demonstrating that both IFIT1 and IFIT3 mediate restriction of unmethylated SARS-CoV-2 RNA.\",\n      \"method\": \"Engineered SARS-CoV-2 NSP16 active-site mutant, siRNA knockdown of IFIT1/IFIT3, type I IFN sensitivity assays in vitro, hamster in vivo infection model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using siRNA knockdown in the context of recombinant virus with active-site mutation, replicated in two publications (PMIDs 36722972 and 36285486)\",\n      \"pmids\": [\"36722972\", \"36285486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFIT1 and IFIT5 binding to capped mRNA is strongly influenced by cap structure modifications. The most stable IFIT1 complexes form with GpppG/A- and m7GpppG/A-capped RNAs (cap 0). NAD+- and NADH-capped RNAs associate with IFIT5 with kinetic parameters comparable to pppG-RNA. Modified synthetic cap analogs incorporated into mRNAs partially protect them from IFIT1-mediated translation inhibition.\",\n      \"method\": \"Kinetic binding analysis (surface plasmon resonance or equivalent biophysical methods) of IFIT1/IFIT5 interactions with diverse RNA substrates, in vitro translation inhibition assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic kinetic binding measurements across multiple RNA substrates plus translation assays, single lab\",\n      \"pmids\": [\"31658992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ifit1 does not directly inhibit norovirus translation (which uses a VPg cap substitute that is refractory to Ifit1) but restricts norovirus replication by stimulating interferon-beta expression downstream of cytoplasmic RNA sensing (but not TLR3/TLR4 signaling). Ifit1-KO cells showed enhanced norovirus replication.\",\n      \"method\": \"CRISPR-Cas9 Ifit1 knockout RAW264.7 cells, virus yield assay, in vitro Ifit1-mediated translation inhibition assay with VPg-linked RNA, qPCR for IFN-β induction after poly(I:C) transfection vs. TLR stimulation\",\n      \"journal\": \"Wellcome open research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple functional readouts (viral yield, in vitro translation, signaling), single lab\",\n      \"pmids\": [\"31372503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IFIT1 interacts with Rho/Rac guanine nucleotide exchange factor (GEF) as identified by GST-pulldown from SLE patient white blood cell lysate and MALDI-TOF mass spectrometry.\",\n      \"method\": \"GST-IFIT1 fusion protein pulldown from patient cell lysate, MALDI-TOF mass spectrometry identification of binding partner\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown without reciprocal validation or functional follow-up, single lab\",\n      \"pmids\": [\"12777642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Poxvirus ankyrin protein LSDV012 interacts with IFIT1, alters its subcellular localization, binds its C-terminus, and inhibits its RNA-binding ability without inducing IFIT1 degradation, thereby antagonizing IFIT1-mediated antiviral restriction in a host-species-specific manner.\",\n      \"method\": \"Co-immunoprecipitation of LSDV012 with IFIT1, subcellular localization imaging, RNA-binding inhibition assays, LSDV012-deletion virus growth assays in IFN-treated cells, phylogenetic analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with localization and functional RNA-binding assays and virus genetic deletion, single lab\",\n      \"pmids\": [\"40096184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Amino acids 364 and 366 of IFIT1 are sufficient to determine differential anti-VEEV activity between human and chimpanzee IFIT1 (which differ at only 8 positions). Human and bat (black flying fox) IFIT1 strongly bind cap 0 RNA and inhibit VEEV, while chimpanzee IFIT1 does not, despite near-identity. Position 366 is a rapidly evolving residue under positive selection.\",\n      \"method\": \"Mutagenesis of human IFIT1 (positions 364/366), VEEV infection assays, cap 0 RNA-binding assays across 39 mammalian IFIT1 orthologs, evolutionary analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis combined with functional assays across 39 orthologs, published in peer-reviewed journal, rigorous structure-function analysis\",\n      \"pmids\": [\"41123582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"When IFIT1 is expressed at high levels in the absence of IFIT3, it can inhibit translation of certain 'self' IFN-stimulated gene mRNAs including ISG15 and IFITM1. IFIT1:IFIT3 complex formation rescues ISG15 and IFITM1 from IFIT1-mediated translation inhibition. IFIT1 is degraded by the proteasome in the absence of IFIT3; direct binding to IFIT3 protects IFIT1 from proteasomal degradation, ensuring IFIT1 accumulation only when IFIT3 is co-expressed.\",\n      \"method\": \"IFIT3-knockout cells, proteasome inhibitor treatment, in vitro translation assays, viral (Semliki Forest virus) infection assays, overexpression experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with multiple functional readouts and proteasome inhibitor rescue, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.17.688928\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An MST-based binding assay revealed that the m6Am cap modification (5'-terminal m6A mark in the m7G cap) protects RNA from IFIT1 binding in an additive manner with 2'O-methylation (cap 1). Several noncanonical RNA caps, including trimethylguanosine, unmethylated G-cap, and FAD caps, bind IFIT1 with increased affinity compared to cap 1 RNA. m6A in the 5'UTR (not at the cap-adjacent position) is not recognized by IFIT proteins.\",\n      \"method\": \"Microscale thermophoresis (MST) binding assay with fluorescently labeled IFIT1 and 13 distinct RNA substrates\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic biophysical binding assay with multiple RNA substrates, single lab, single method\",\n      \"pmids\": [\"39643445\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFIT1 is an interferon-stimulated antiviral protein that forms a positively charged RNA-binding tunnel (structurally defined at 1.6 Å) to selectively recognize and bind viral RNAs bearing cap 0 (unmethylated 2'O on first nucleotide) or 5'-triphosphate structures with high affinity, competing with eIF4F (specifically the eIF3 complex) to block translation of foreign mRNAs; IFIT3 binding to IFIT1's C-terminus allosterically enhances cap-0 specificity, stabilizes IFIT1 by protecting it from proteasomal degradation, and prevents IFIT1 from aberrantly targeting self ISG mRNAs; IFIT1 also acts as a negative-feedback regulator of antiviral signaling by binding MITA/STING and disrupting its interactions with VISA and TBK1, and in the nucleus modulates inflammatory vs. interferon gene programs via a Sin3A-HDAC2 complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFIT1 is an interferon-stimulated antiviral effector that discriminates foreign from self mRNA by sensing the chemistry of the 5' cap and the triphosphate terminus, then blocking translation of the bound RNA [#1, #7]. It binds 5'-triphosphate RNA with nanomolar affinity through an arginine-rich C-terminal groove (R187) [#0], but binds cap-0 (2'O-unmethylated) capped RNA roughly an order of magnitude more tightly, making cap-0 recognition its dominant activity [#1, #13]. A 1.6 Å crystal structure resolves a water-filled, positively charged RNA-binding tunnel whose hydrophobic extension engages the cap in syn and anti conformations; cap-proximal nucleotides supply the affinity needed to outcompete eIF4F, and N1/N2 2'O-methylation sterically interfere with binding, providing the molecular basis for self/nonself discrimination [#4]. Sequestration of cap-0 or triphosphate RNA, together with binding to the eIF3e subunit, prevents translation initiation by impairing eIF3-dependent stabilization of the eIF2·GTP·Met-tRNAi ternary complex [#3, #1]. Through this mechanism IFIT1 restricts viruses that fail to fully cap-methylate their RNA, including coronaviruses, alphaviruses, and rubulaviruses, with antiviral potency tracking the 2'O-methylation status of the viral 5' end [#4, #16, #12, #11]. IFIT1 specificity and stability are governed by IFIT3: IFIT3 binds the IFIT1 C-terminus via a YxxxL motif, extends IFIT1 half-life by protecting it from proteasomal degradation, and allosterically sharpens IFIT1's preference for cap-0 RNA, preventing aberrant targeting of self ISG mRNAs such as ISG15 and IFITM1 [#5, #6]. Human IFIT1 and rodent Ifit1 (IFIT1B) are functionally divergent paralogs with distinct cap-methyltransferase specificities, and rapidly evolving residues (e.g., positions 364/366) under positive selection tune antiviral activity across mammals [#8, #21]. Beyond cap-dependent translational restriction, IFIT1 negatively regulates antiviral signaling by binding MITA/STING and disrupting its association with VISA and TBK1 [#2], and acts in the nucleus to modulate inflammatory versus interferon gene programs via a Sin3A-HDAC2 complex [#9]. Viruses counter IFIT1 by direct antagonism, including HEV RdRp sequestration and poxvirus ankyrin protein interference with RNA binding [#15, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first molecular mechanism for IFIT1-mediated translational shutdown by identifying eIF3 as a direct target, answering how an ISG could block initiation.\",\n      \"evidence\": \"Co-IP with eIF3 subunits and in vitro translation inhibition assays\",\n      \"pmids\": [\"16973618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect eIF3 binding to RNA-substrate selectivity\", \"Relative contribution of eIF3e binding vs. RNA sequestration to inhibition unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a non-translational role for IFIT1 as a negative-feedback brake on type I IFN signaling, showing it does not only act as an effector but also tunes the response.\",\n      \"evidence\": \"Reciprocal/competitive co-IP with MITA/STING, IFN-β reporter and VSV rescue assays\",\n      \"pmids\": [\"19416887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without structural mapping of the MITA interface\", \"Relationship between this signaling role and cap-binding activity not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined IFIT1 as a direct PPP-RNA sensor with a specific arginine determinant (R187), establishing the C-terminal charged groove as the RNA-binding site and linking sequestration to viral restriction.\",\n      \"evidence\": \"Affinity proteomics with PPP-RNA bait, affinity measurements, R187 mutagenesis, Ifit1-KO mouse infection\",\n      \"pmids\": [\"21642987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet establish cap-0 as the preferred ligand\", \"Roles of IFIT2/IFIT3 within the complex not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Redefined IFIT1's principal ligand as cap-0 (2'O-unmethylated) capped RNA, explaining how it discriminates self (2'O-methylated) from viral mRNA and competes with translation initiation factors.\",\n      \"evidence\": \"AP-MS, pulsed SILAC-MS, in vitro competition translation assays, and Ifit1-KO cell/virus models (human and mouse)\",\n      \"pmids\": [\"24098121\", \"23824812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cap-0 vs. cap-1 discrimination not yet resolved\", \"Species-specific complex composition only partially defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed human IFIT1 and mouse Ifit1/IFIT1B are deeply diverged paralogs with distinct cap-methyltransferase specificities, cautioning against direct cross-species mechanistic extrapolation.\",\n      \"evidence\": \"Phylogenetics, yeast genetic complementation, and comparative virological assays\",\n      \"pmids\": [\"27240734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residue-level determinants of the divergence not pinpointed in this study\", \"Functional consequences for cellular host range incompletely mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the high-resolution structural mechanism: a positively charged RNA-binding tunnel that engages the cap and uses 2'O-methylation as a steric exclusion signal, defining self/nonself recognition at atomic resolution.\",\n      \"evidence\": \"1.6 Å crystal structure of RNA-bound IFIT1, gel-shift binding, in vitro translation, structure-guided mutagenesis, coronavirus infection\",\n      \"pmids\": [\"28251928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How accessory IFIT proteins reshape the tunnel not addressed\", \"Conformational dynamics in solution inferred indirectly\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified IFIT3 as a regulator that binds the IFIT1 C-terminus via a YxxxL motif, stabilizing IFIT1 and allosterically enhancing its cap-0 specificity, explaining how the complex avoids self-mRNA targeting.\",\n      \"evidence\": \"Crystal structure of the IFIT1-IFIT3 C-terminal complex on cap-0 RNA, reconstitution, motif mutagenesis, half-life and translation assays\",\n      \"pmids\": [\"29525521\", \"29554348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of higher-order IFIT1/IFIT2/IFIT3 assemblies in cells incompletely defined\", \"Degradation pathway protected by IFIT3 not molecularly identified in these studies\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a distinct nuclear function for IFIT1 in shaping inflammatory vs. interferon gene programs, expanding its role beyond cytoplasmic translation control.\",\n      \"evidence\": \"Genome-wide siRNA screen, RNA-seq, ChIP showing association with Sin3A-HDAC2, and subcellular fractionation\",\n      \"pmids\": [\"30282041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IFIT1 nuclear import unknown\", \"Direct vs. indirect recruitment to chromatin not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantified IFIT1 substrate hierarchy (cap-0 >> 5'-ppp) and mapped its antiviral scope, establishing why negative-sense RNA viruses presenting 5'-ppp escape restriction while 5'UTR features tune sensitivity.\",\n      \"evidence\": \"Ifit1-KO/CRISPR cells and mice across multiple viral families, 5'UTR chimeras, and binding-affinity measurements\",\n      \"pmids\": [\"26157117\", \"25927359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"cis-acting 5'UTR determinants of sensitivity not fully defined\", \"IFIT1-independent inhibitory mechanisms remain uncharacterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systematically mapped how diverse cap chemistries modulate IFIT1 binding, refining the self/nonself code and revealing potential mRNA-therapeutic escape strategies.\",\n      \"evidence\": \"Kinetic biophysical binding analyses of IFIT1/IFIT5 across diverse RNA caps plus translation assays\",\n      \"pmids\": [\"31658992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of noncanonical caps (NAD+/NADH) not established\", \"Single-lab biophysical measurements\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the cap-recognition code to m6Am and other noncanonical modifications, showing m6Am acts additively with cap-1 2'O-methylation to exclude IFIT1.\",\n      \"evidence\": \"MST binding assays with 13 RNA substrates\",\n      \"pmids\": [\"39643445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single biophysical method without cellular/translation validation for all substrates\", \"Structural basis of m6Am exclusion not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated in pathogen-relevant context that SARS-CoV-2 NSP16 2'O-methylation shields viral RNA from both IFIT1 and IFIT3, validating the self/nonself cap model genetically during a major outbreak.\",\n      \"evidence\": \"Recombinant NSP16 active-site mutant virus, siRNA knockdown of IFIT1/IFIT3, IFN-sensitivity assays, hamster infection\",\n      \"pmids\": [\"36722972\", \"36285486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate IFIT1 vs. IFIT3 individual contributions cleanly\", \"Knockdown rather than complete knockout\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pinpointed rapidly evolving residues (364/366) that determine antiviral activity across mammalian orthologs, providing a molecular handle on positive selection at the IFIT1 host-virus interface.\",\n      \"evidence\": \"Mutagenesis of human IFIT1, VEEV infection and cap-0 binding assays across 39 orthologs, evolutionary analysis\",\n      \"pmids\": [\"41123582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which position 366 alters function not solved\", \"Generalizability beyond VEEV/alphaviruses untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that uncomplexed IFIT1 can aberrantly inhibit self ISG mRNAs and is proteasomally degraded, while IFIT3 binding both stabilizes IFIT1 and prevents self-targeting, integrating stability and specificity control.\",\n      \"evidence\": \"IFIT3-KO cells, proteasome inhibition, in vitro translation, and SFV infection (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.17.688928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"E3 ligase/degron mediating IFIT1 turnover not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a viral antagonism mechanism in which poxvirus ankyrin protein LSDV012 binds the IFIT1 C-terminus and blocks RNA binding without triggering degradation, illustrating direct effector neutralization.\",\n      \"evidence\": \"Co-IP, localization imaging, RNA-binding inhibition assays, and LSDV012-deletion virus growth in IFN-treated cells\",\n      \"pmids\": [\"40096184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural details of the LSDV012-IFIT1 interface unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFIT1's distinct activities — cytoplasmic cap-dependent translation inhibition, STING-mediated signaling feedback, and nuclear Sin3A-HDAC2 transcriptional modulation — are coordinated within a cell and what governs IFIT1 nuclear import remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IFIT1 nuclear localization unknown\", \"No integrated model linking RNA-binding and signaling/transcriptional roles\", \"E3 ligase governing IFIT1 turnover unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 4, 7, 17, 23]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [1, 3, 10, 11]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 16, 15, 20]}\n    ],\n    \"complexes\": [\"IFIT1-IFIT3 heterodimer\", \"IFIT1/IFIT2/IFIT3 complex\", \"Sin3A-HDAC2 complex (nuclear)\"],\n    \"partners\": [\"IFIT3\", \"IFIT2\", \"EIF3E\", \"STING1\", \"TBK1\", \"AXIN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}