Affinage

IFIT1

Antiviral innate immune response effector IFIT1 · UniProt P09914

Length
478 aa
Mass
55.4 kDa
Annotated
2026-06-10
81 papers in source corpus 25 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2006 Medium

    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

    PMID:16973618

    Open questions at the time
    • Did not connect eIF3 binding to RNA-substrate selectivity
    • Relative contribution of eIF3e binding vs. RNA sequestration to inhibition unresolved
  2. 2009 Medium

    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

    PMID:19416887

    Open questions at the time
    • Single lab without structural mapping of the MITA interface
    • Relationship between this signaling role and cap-binding activity not addressed
  3. 2011 High

    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

    PMID:21642987

    Open questions at the time
    • Did not yet establish cap-0 as the preferred ligand
    • Roles of IFIT2/IFIT3 within the complex not mechanistically dissected
  4. 2013 High

    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)

    PMID:23824812 PMID:24098121

    Open questions at the time
    • Structural basis of cap-0 vs. cap-1 discrimination not yet resolved
    • Species-specific complex composition only partially defined
  5. 2016 High

    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

    PMID:27240734

    Open questions at the time
    • Residue-level determinants of the divergence not pinpointed in this study
    • Functional consequences for cellular host range incompletely mapped
  6. 2017 High

    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

    PMID:28251928

    Open questions at the time
    • How accessory IFIT proteins reshape the tunnel not addressed
    • Conformational dynamics in solution inferred indirectly
  7. 2018 High

    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

    PMID:29525521 PMID:29554348

    Open questions at the time
    • Stoichiometry of higher-order IFIT1/IFIT2/IFIT3 assemblies in cells incompletely defined
    • Degradation pathway protected by IFIT3 not molecularly identified in these studies
  8. 2018 Medium

    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

    PMID:30282041

    Open questions at the time
    • Mechanism of IFIT1 nuclear import unknown
    • Direct vs. indirect recruitment to chromatin not resolved
  9. 2015 High

    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

    PMID:25927359 PMID:26157117

    Open questions at the time
    • cis-acting 5'UTR determinants of sensitivity not fully defined
    • IFIT1-independent inhibitory mechanisms remain uncharacterized
  10. 2019 Medium

    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

    PMID:31658992

    Open questions at the time
    • In vivo relevance of noncanonical caps (NAD+/NADH) not established
    • Single-lab biophysical measurements
  11. 2025 Medium

    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

    PMID:39643445

    Open questions at the time
    • Single biophysical method without cellular/translation validation for all substrates
    • Structural basis of m6Am exclusion not determined
  12. 2022 High

    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

    PMID:36285486 PMID:36722972

    Open questions at the time
    • Did not separate IFIT1 vs. IFIT3 individual contributions cleanly
    • Knockdown rather than complete knockout
  13. 2025 High

    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

    PMID:41123582

    Open questions at the time
    • Structural mechanism by which position 366 alters function not solved
    • Generalizability beyond VEEV/alphaviruses untested
  14. 2025 Medium

    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)

    PMID:bio_10.1101_2025.11.17.688928

    Open questions at the time
    • Preprint not yet peer-reviewed
    • E3 ligase/degron mediating IFIT1 turnover not identified
  15. 2025 Medium

    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

    PMID:40096184

    Open questions at the time
    • Structural details of the LSDV012-IFIT1 interface unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • Mechanism of IFIT1 nuclear localization unknown
  • No integrated model linking RNA-binding and signaling/transcriptional roles
  • E3 ligase governing IFIT1 turnover unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0045182 translation regulator activity 4 GO:0098772 molecular function regulator activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-8953854 Metabolism of RNA 3
Partners
AXIN1EIF3EIFIT2IFIT3STING1TBK1
Complex memberships
IFIT1-IFIT3 heterodimerIFIT1/IFIT2/IFIT3 complexSin3A-HDAC2 complex (nuclear)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Affinity proteomics with PPP-RNA bait, binding affinity measurements, site-directed mutagenesis (R187), Ifit1-knockout mouse infection experiments Nature immunology High 21642987
2013 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. Proteome-wide affinity purification coupled to mass spectrometry, pulsed SILAC-MS, in vitro competition translation assays, functional validation with viral infection models PLoS pathogens High 24098121
2009 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. Co-immunoprecipitation, competitive co-IP, overexpression/knockdown experiments, IFN-β promoter reporter assay, VSV replication rescue assay Proceedings of the National Academy of Sciences of the United States of America Medium 19416887
2006 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. Co-immunoprecipitation with eIF3 subunits, in vitro translation inhibition assays The Journal of biological chemistry Medium 16973618
2017 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. X-ray crystallography, gel-shift binding assays, in vitro translation assays, structure-guided mutagenesis, coronavirus infection experiments Proceedings of the National Academy of Sciences of the United States of America High 28251928
2018 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. Crystal structure of IFIT1-IFIT3 C-terminal domain complex bound to cap 0 RNA, biochemical binding assays, genetic studies in cells, half-life measurements Immunity High 29525521
2018 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. In vitro reconstitution of IFIT complexes, co-IP, motif mutagenesis (YxxxL), cap 0 RNA-binding assays, in vitro translation inhibition assays Nucleic acids research High 29554348
2013 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. Ifit1 knockout MEFs and macrophages, viral replication assays, in vitro RNA-binding assays, in vitro translation inhibition assays Journal of virology High 23824812
2016 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. Evolutionary/phylogenetic analysis, yeast genetic complementation assay, virological infection assays comparing IFIT1 and IFIT1B eLife High 27240734
2018 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. 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 Cell reports Medium 30282041
2012 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. IFN treatment followed by metabolic labeling of viral vs. cellular proteins, IFIT1 knockdown/rescue, in vitro translation assays with purified IFIT1 The Journal of general virology Medium 23052390
2016 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. In vitro translation with purified human IFIT1, biochemical 2'O methylation of mRNAs with purified capping enzymes, cell-based coinfection assays Journal of virology High 27512068
2015 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. IFIT1-knockout cells, IFN-β treatment, single-cycle infection assays, 5'UTR chimeric virus constructs, type I IFN induction measurements PLoS pathogens Medium 25927359
2015 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. 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 of virology High 26157117
2015 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. Co-immunoprecipitation of Ifit1 with Axin, adeno-associated virus-mediated liver-targeted Ifit1 overexpression in mice, JNK phosphorylation assays, apoptosis assays The Journal of infectious diseases Medium 26459629
2019 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. Co-immunoprecipitation of HEV RdRp with IFIT1, overexpression/knockdown of IFIT1 in hepatoma cells, viral replication assays, in vitro translation inhibition assays The Journal of general virology Medium 30702423
2022 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. 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 of virology High 36285486 36722972
2019 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. Kinetic binding analysis (surface plasmon resonance or equivalent biophysical methods) of IFIT1/IFIT5 interactions with diverse RNA substrates, in vitro translation inhibition assays RNA (New York, N.Y.) Medium 31658992
2019 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. 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 Wellcome open research Medium 31372503
2003 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. GST-IFIT1 fusion protein pulldown from patient cell lysate, MALDI-TOF mass spectrometry identification of binding partner Rheumatology (Oxford, England) Low 12777642
2025 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. Co-immunoprecipitation of LSDV012 with IFIT1, subcellular localization imaging, RNA-binding inhibition assays, LSDV012-deletion virus growth assays in IFN-treated cells, phylogenetic analysis PLoS pathogens Medium 40096184
2025 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. Mutagenesis of human IFIT1 (positions 364/366), VEEV infection assays, cap 0 RNA-binding assays across 39 mammalian IFIT1 orthologs, evolutionary analysis eLife High 41123582
2025 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. IFIT3-knockout cells, proteasome inhibitor treatment, in vitro translation assays, viral (Semliki Forest virus) infection assays, overexpression experiments bioRxivpreprint Medium bio_10.1101_2025.11.17.688928
2025 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. Microscale thermophoresis (MST) binding assay with fluorescently labeled IFIT1 and 13 distinct RNA substrates RNA (New York, N.Y.) Medium 39643445

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. Nature immunology 410 21642987
2010 The ISG56/IFIT1 gene family. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 246 20950130
2013 Sequestration by IFIT1 impairs translation of 2'O-unmethylated capped RNA. PLoS pathogens 179 24098121
2009 ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. Proceedings of the National Academy of Sciences of the United States of America 176 19416887
2012 2'-O methylation of the viral mRNA cap by West Nile virus evades ifit1-dependent and -independent mechanisms of host restriction in vivo. PLoS pathogens 144 22589727
2006 Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56. The Journal of biological chemistry 139 16973618
2011 ISG56 and IFITM1 proteins inhibit hepatitis C virus replication. Journal of virology 129 21976647
2006 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. Journal of virology 113 17079283
2021 Cancer-associated fibroblast-derived CXCL11 modulates hepatocellular carcinoma cell migration and tumor metastasis through the circUBAP2/miR-4756/IFIT1/3 axis. Cell death & disease 110 33707417
2018 Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability. Immunity 106 29525521
2017 Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations. Proceedings of the National Academy of Sciences of the United States of America 103 28251928
2013 Ifit1 inhibits Japanese encephalitis virus replication through binding to 5' capped 2'-O unmethylated RNA. Journal of virology 99 23824812
2014 IFIT1: A dual sensor and effector molecule that detects non-2'-O methylated viral RNA and inhibits its translation. Cytokine & growth factor reviews 93 24909568
2015 IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. PLoS pathogens 92 25927359
2018 IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA. Nucleic acids research 90 29554348
2019 IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling. Oncogene 84 30626937
2018 IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages. Cell reports 84 30282041
2016 Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals. eLife 81 27240734
2003 Protein interaction for an interferon-inducible systemic lupus associated gene, IFIT1. Rheumatology (Oxford, England) 62 12777642
1996 The glucocorticoid attenuated response genes GARG-16, GARG-39, and GARG-49/IRG2 encode inducible proteins containing multiple tetratricopeptide repeat domains. Archives of biochemistry and biophysics 57 8660659
2007 Tissue-specific and inducer-specific differential induction of ISG56 and ISG54 in mice. Journal of virology 56 17553874
2022 Fusobacterium nucleatum stimulates cell proliferation and promotes PD-L1 expression via IFIT1-related signal in colorectal cancer. Neoplasia (New York, N.Y.) 53 36371909
1994 Structure, chromosome localization, and regulation of expression of the interferon-regulated mouse Ifi54/Ifi56 gene family. Genomics 51 7896268
2022 Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction. EMBO reports 43 36285486
2015 Human and Murine IFIT1 Proteins Do Not Restrict Infection of Negative-Sense RNA Viruses of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families. Journal of virology 42 26157117
2020 Annexin-A1 promotes RIG-I-dependent signaling and apoptosis via regulation of the IRF3-IFNAR-STAT1-IFIT1 pathway in A549 lung epithelial cells. Cell death & disease 41 32541772
2023 SARS-CoV-2 Uses Nonstructural Protein 16 To Evade Restriction by IFIT1 and IFIT3. Journal of virology 39 36722972
2012 ISG56/IFIT1 is primarily responsible for interferon-induced changes to patterns of parainfluenza virus type 5 transcription and protein synthesis. The Journal of general virology 39 23052390
2020 Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway. Oncotarget 34 32499867
2022 circ_0086296 induced atherosclerotic lesions via the IFIT1/STAT1 feedback loop by sponging miR-576-3p. Cellular & molecular biology letters 33 36138395
2016 Human IFIT1 Inhibits mRNA Translation of Rubulaviruses but Not Other Members of the Paramyxoviridae Family. Journal of virology 33 27512068
2013 MicroRNA profiling of Sendai virus-infected A549 cells identifies miR-203 as an interferon-inducible regulator of IFIT1/ISG56. Journal of virology 32 23785202
2012 Identification and validation of Ifit1 as an important innate immune bottleneck. PloS one 30 22745654
2014 ISG54 and ISG56 are induced by TLR3 signaling in U373MG human astrocytoma cells: possible involvement in CXCL10 expression. Neuroscience research 25 24630834
2015 Interferon-stimulated gene (ISG) 60, as well as ISG56 and ISG54, positively regulates TLR3/IFN-β/STAT1 axis in U373MG human astrocytoma cells. Neuroscience research 24 26423178
2013 MDA5 and ISG56 mediate CXCL10 expression induced by toll-like receptor 4 activation in U373MG human astrocytoma cells. Neuroscience research 22 23684765
2021 IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/β-catenin signaling. Cellular oncology (Dordrecht, Netherlands) 21 34791638
2022 COL8A1 Promotes NSCLC Progression Through IFIT1/IFIT3-Mediated EGFR Activation. Frontiers in oncology 18 35280763
2019 Hepatitis E virus polymerase binds to IFIT1 to protect the viral RNA from IFIT1-mediated translation inhibition. The Journal of general virology 18 30702423
2019 Kinetic analysis of IFIT1 and IFIT5 interactions with different native and engineered RNAs and its consequences for designing mRNA-based therapeutics. RNA (New York, N.Y.) 18 31658992
2016 Antiviral effects of IFIT1 in human cytomegalovirus-infected fetal astrocytes. Journal of medical virology 18 27589693
2018 A Talented Duo: IFIT1 and IFIT3 Patrol Viral RNA Caps. Immunity 17 29562196
2015 Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway. The Journal of infectious diseases 17 26459629
2017 HPV16 E6 and E7 Upregulate Interferon-Induced Antiviral Response Genes ISG15 and IFIT1 in Human Trophoblast Cells. Pathogens (Basel, Switzerland) 15 28869524
2019 Ifit1 regulates norovirus infection and enhances the interferon response in murine macrophage-like cells. Wellcome open research 14 31372503
2018 IFIT1 Expression Patterns Induced by H9N2 Virus and Inactivated Viral Particle in Human Umbilical Vein Endothelial Cells and Bronchus Epithelial Cells. Molecules and cells 14 29629559
2001 Lipopolysaccharide-induced switch between retinoid receptor (RXR) alpha and glucocorticoid attenuated response gene (GARG)-16 messenger RNAs in cultured rat microglia. Journal of neuroscience research 13 11398178
2024 Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis. Cancer letters 12 38462032
2024 IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC). Journal of translational medicine 12 38898490
2020 Lipopolysaccharide Promotes Inflammatory Response via Enhancing IFIT1 Expression in Human Umbilical Vein Endothelial Cells. DNA and cell biology 12 32551893
2025 A poxvirus ankyrin protein LSDV012 inhibits IFIT1 in a host-species-specific manner by compromising its RNA binding ability. PLoS pathogens 11 40096184
2008 Common Variation in the CYP17A1 and IFIT1 Genes on Chromosome 10 Does Not Contribute to the Risk of Endometriosis. The open reproductive science journal 11 20411041
2022 Simultaneous Detection of RIG-1, MDA5, and IFIT-1 Expression Is a Convenient Tool for Evaluation of the Interferon-Mediated Response. Viruses 10 36298646
2024 IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/β-catenin signaling. Cellular oncology (Dordrecht, Netherlands) 9 38536650
2024 Single-cell transcriptomics of blood identified IFIT1+ neutrophil subcluster expansion in NTM-PD patients. International immunopharmacology 9 38901242
2023 Lysyl oxidase-like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3. Cancer science 9 37496288
2022 Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) accelerates osteoclast formation by regulating signal transducer and activator of transcription 3 (STAT3) signalling. Bioengineered 9 35034537
2017 Interferon-induced protein 56 (IFI56) is induced by VHSV infection but not by bacterial infection in olive flounder (Paralichthys olivaceus). Fish & shellfish immunology 9 28499966
2016 The association between expression of IFIT1 in podocytes of MRL/lpr mice and the renal pathological changes it causes: An animal study. Oncotarget 9 27823966
2016 IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection. World journal of gastroenterology 9 27956805
2022 Overexpression of IFIT1 protects against LPS-induced acute lung injury via regulating CCL5-p65NF-κB signaling. International immunopharmacology 8 36446235
2020 ISG56 is involved in CXCL10 expression induced by TLR3 signaling in BEAS-2B bronchial epithelial cells. Experimental lung research 8 32363951
2019 Grouper IFIT1 inhibits iridovirus and nodavirus infection by positively regulating interferon response. Fish & shellfish immunology 8 31476389
2023 Kruppel-like factor 13 acts as a tumor suppressor in thyroid carcinoma by downregulating IFIT1. Biology direct 7 37817224
2022 The Highly Expressed IFIT1 in Nasopharyngeal Carcinoma Enhances Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma Cells. Molecular biotechnology 6 35038119
2025 The Cap-proximal secondary structures of the 5'UTRs of parainfluenza virus 5 mRNAs specify differential sensitivity to type I interferon and IFIT1. The Journal of general virology 4 40146622
2025 IFIT1 is rapidly evolving and exhibits disparate antiviral activities across 11 mammalian orders. eLife 4 41123582
2014 Loop de loop: viral RNA evades IFIT1 targeting. Trends in microbiology 4 24630528
2025 IFIT1 is rapidly evolving and exhibits disparate antiviral activities across 11 mammalian orders. bioRxiv : the preprint server for biology 3 38798375
2025 Downregulation of PAX1 in OSCC Enhances Stemness and Immunosuppression via IFIT1 and PD-L1 Pathways. Oral diseases 3 39748231
2024 TMEM2 suppresses TLR3-mediated IFN-β/ISG56/CXCL10 expression in BEAS-2B bronchial epithelial cells. Molecular biology reports 3 38483660
2022 Bioinformation Analysis Reveals IFIT1 as Potential Biomarkers in Central Nervous System Tuberculosis. Infection and drug resistance 3 35027832
2003 [Using GST-tag to capture protein interaction of an interferon-inducible systemic lupus associated gene, IFIT1]. Zhonghua yi xue za zhi 2 12899756
2026 Pathogenic Ifit1 + neutrophils driven by IRF7 promote liver injury and represent a therapeutic target in acute liver failure. Hepatology (Baltimore, Md.) 1 41911548
2025 An MST-based assay reveals new binding preferences of IFIT1 for canonically and noncanonically capped RNAs. RNA (New York, N.Y.) 1 39643445
2022 SARS-CoV-2 Uses Nonstructural Protein 16 to Evade Restriction by IFIT1 and IFIT3. bioRxiv : the preprint server for biology 1 36203546
2019 In silico structure analysis of alphaviral RNA genomes shows diversity in the evasion of IFIT1-mediated innate immunity. Journal of biosciences 1 31502557
2026 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. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41479373
2026 Arecoline-induced EV-mediated ZNF582 hypermethylation drives IFIT1-PD-L1 immune evasion in oral squamous cell carcinoma. Clinical epigenetics 0 42185863
2025 Transcriptomic analysis reveals TME-mediated macrophage IFIT1 upregulation and CX3CR1 suppression drive osteosarcoma progression. Frontiers in oncology 0 41267985
2010 [Expression of ifi56 gene in ATRA-induced APL cell differentiation and construction of ifi56 gene eukaryotic expression plasmid]. Zhongguo shi yan xue ye xue za zhi 0 21129252

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