{"gene":"IFIT2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2025,"finding":"Cryo-EM structure of the IFIT2-IFIT3 complex at 3.2 Å reveals a domain-swapped heterodimer; this complex recognizes viral mRNAs bearing short 5' UTRs (<50 nucleotides) as a molecular pattern for innate immune recognition, inhibits their translation, and confers antiviral activity against viruses such as VSV and parainfluenza virus 3.","method":"Cryo-EM structure determination (3.2 Å), in vitro translation inhibition assays, antiviral activity assays with recombinant viruses, 5' UTR length-swap reporter experiments","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at 3.2 Å combined with functional translation inhibition and antiviral assays; independently supported by preprint (bio_10.1101_2025.02.11.637299) using same methods","pmids":["41093992"],"is_preprint":false},{"year":2025,"finding":"IFIT2-IFIT3 heterodimer binds directly to the VEEV 3' UTR in vitro; 5' UTR lengths <50 nucleotides are necessary and sufficient for translation inhibition by the IFIT2-IFIT3 complex, independent of cap structure.","method":"In vitro RNA-binding assays, recombinant VEEV clones with swapped 3' UTRs, in vitro translation inhibition assays","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus viral infection experiments in single study, consistent with structural data from PMID 41093992","pmids":["40079162"],"is_preprint":false},{"year":2018,"finding":"IFIT1 and IFIT3 interact via a YxxxL motif in their C-termini; IFIT2 and IFIT3 form homodimers that dissociate to yield a more stable IFIT2-IFIT3 heterodimer, which also associates with IFIT1. IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to cap0 Zika virus reporter mRNA, and enhances IFIT1-mediated translation inhibition.","method":"In vitro reconstitution of IFIT complexes, cap0 mRNA-binding assay, translation inhibition assay, site-directed mutagenesis of YxxxL motif","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis and multiple functional readouts in a single rigorous study","pmids":["29554348"],"is_preprint":false},{"year":2020,"finding":"IFIT2 binds directly to viral and cellular mRNAs in AU-rich regions (demonstrated by CLIP-seq during influenza virus infection); ribosome/polysome profiling showed that IFIT2 prevents ribosome pausing on bound mRNAs, thereby enhancing translational efficiency. Influenza virus repurposes this activity to promote viral mRNA translation and replication.","method":"CLIP-seq, polysome profiling, ribosome profiling, CRISPR-Cas9 knockout screen","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal transcriptomic methods (CLIP-seq, polysome and ribosome profiling) with functional CRISPR validation in a single rigorous study","pmids":["32839537"],"is_preprint":false},{"year":2024,"finding":"IFIT2 RNA-binding activity is essential for its antiviral function in vivo: mice expressing a mutant IFIT2 that cannot bind RNA were as susceptible to intranasal VSV infection as Ifit2−/− mice. Additionally, neuron-specific conditional knockout of Ifit2 was sufficient to render mice susceptible to VSV neuropathogenesis via the intranasal (but not subcutaneous) route, placing IFIT2 function specifically in neurons.","method":"Conditional knockout mouse (neuron-specific Cre), RNA-binding mutant knock-in mouse, intranasal/subcutaneous VSV challenge, survival and viral load analysis","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent genetically modified mouse lines with functional in vivo readouts, loss-of-function with specific mechanistic test (RNA-binding mutant)","pmids":["38888342"],"is_preprint":false},{"year":2006,"finding":"GARG39/IFIT2 protein interacts with microtubules in vitro, co-localizes with β-tubulin in vivo, and is enriched in the mitotic spindle of non-neuronal cells undergoing mitosis, identifying it as a microtubule-associated protein.","method":"In vitro microtubule binding assay, immunofluorescence co-localization with β-tubulin, mitotic cell imaging","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assay combined with immunofluorescence co-localization, single lab","pmids":["17030862"],"is_preprint":false},{"year":2017,"finding":"Proteasome inhibition blocks IFIT2 degradation and causes IFIT2 to aggregate at the centrosome; this aggregation depends on intact microtubule dynamics (colchicine-sensitive) and dynein activity (ciliobrevin-sensitive). IFIT2 combined with proteasome inhibitor synergistically induces cancer cell apoptosis.","method":"Immunofluorescence localization after proteasome inhibitor treatment, pharmacological inhibition of microtubules (colchicine) and dynein (ciliobrevin), apoptosis assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with pharmacological perturbations and functional apoptosis readout, single lab","pmids":["28367102"],"is_preprint":false},{"year":2018,"finding":"IFIT2 is a binding partner of p67phox, a critical regulatory subunit of NADPH oxidase; loss of IFIT2 increases ROS production by leukocytes, suggesting IFIT2 suppresses NADPH oxidase activation. Ifit2 knockout mice showed improved survival and reduced fungal burden in a systemic Candida albicans model.","method":"Co-immunoprecipitation/binding partner identification, ROS measurement in Ifit2-knockout leukocytes, in vivo C. albicans infection survival study","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding identified plus functional leukocyte assay in KO mice, single lab, two orthogonal methods","pmids":["29666281"],"is_preprint":false},{"year":2013,"finding":"Ifit2 deficiency in macrophages impairs IFN-α/β mRNA and protein production following MHV coronavirus infection, placing Ifit2 as a positive regulator of IFN-α/β induction (rather than solely a direct antiviral effector) in macrophages during coronavirus CNS infection.","method":"Ifit2−/− mouse model, ex vivo microglia/macrophage analysis, IFN-α/β mRNA and protein quantification in bone marrow-derived macrophages, in vivo viral load measurement","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO model with defined cellular phenotype and IFN measurement, single lab","pmids":["24198415"],"is_preprint":false},{"year":2011,"finding":"IKKε phosphorylates STAT1 at serine 708, which is required for IFIT2 expression; loss of IKKε abrogates IFIT2 induction and enhances WNV replication. STAT1 tyrosine dephosphorylation and CRM1-mediated nuclear-cytoplasmic shuttling are prerequisites for Ser-708 phosphorylation. This defines an IFN-induced IKKε→STAT1(Ser708)→IFIT2 signaling axis.","method":"IKKε−/− and IFIT2−/− cell/mouse models, STAT1 phosphorylation analysis (site-specific antibodies), CRM1 inhibitor (leptomycin B) treatment, WNV infection assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with multiple genetic KO models and biochemical phosphorylation analysis, single lab","pmids":["22065572"],"is_preprint":false},{"year":2013,"finding":"IFIT2 promotes IRF3 phosphorylation, thereby amplifying LPS-induced IFN-β production and subsequent IL-6/TNF-α secretion (post-transcriptionally). Ifit2-deficient mice show reduced serum IL-6 and TNF-α and reduced mortality in endotoxin shock. IFIT2 expression is induced in an IFN-α receptor- and IRF9-dependent manner.","method":"Ifit2−/− mouse generation, bone marrow-derived macrophage cytokine assays (ELISA), IRF3 phosphorylation western blotting, LPS endotoxin shock model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined signaling readout (IRF3 phosphorylation) and in vivo phenotype, single lab","pmids":["24014876"],"is_preprint":false},{"year":2008,"finding":"Overexpression of IFIT2 in macrophages selectively reduces LPS-induced TNF-α, IL-6, and MIP-2 expression by decreasing mRNA stability at the post-transcriptional level; characteristics of the 3' UTR of transcripts determine susceptibility to IFIT2-mediated regulation.","method":"Stable IFIT2-overexpressing RAW264.7 macrophage lines, mRNA stability assay (actinomycin D chase), ELISA, western blot","journal":"BMC immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with mRNA stability mechanistic assay, single lab, two orthogonal readouts","pmids":["19108715"],"is_preprint":false},{"year":2012,"finding":"Depletion of IFIT2 in oral squamous cell carcinoma cells activates atypical PKC (aPKC), leading to epithelial-mesenchymal transition, enhanced cell migration, and invasiveness. Inhibition of aPKC (by pseudosubstrate or siRNA) abolished these phenotypes, placing aPKC downstream of IFIT2.","method":"Stable IFIT2 shRNA knockdown cell lines, aPKC pseudosubstrate inhibitor treatment, siRNA knockdown of aPKC, migration/invasion assays, tail-vein metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via chemical and genetic inhibition of aPKC, with functional rescue, single lab","pmids":["22986528"],"is_preprint":false},{"year":2016,"finding":"AJUBA binds directly to the FERM domain of JAK1, dissociating JAK1 from the IFN-γ receptor and thereby inhibiting STAT1 phosphorylation and nuclear translocation, which represses IFIT2 gene expression and inhibits apoptosis in colorectal cancer cells.","method":"Co-immunoprecipitation (AJUBA-JAK1 binding), STAT1 phosphorylation assay, IFIT2 promoter/expression analysis, apoptosis assays, siRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying direct binding partner combined with functional STAT1→IFIT2 pathway dissection, single lab","pmids":["27893714"],"is_preprint":false},{"year":2022,"finding":"METTL3 mediates m6A modification of IFIT2 mRNA, which accelerates IFIT2 mRNA decay in a YTHDF2-dependent manner in intrahepatic cholangiocarcinoma. METTL3 transcription itself is driven by H3K4me3 activation.","method":"METTL3 knockdown/overexpression, MeRIP-seq (m6A mapping), YTHDF2 knockdown rescue experiments, mRNA stability assays, ChIP-seq for H3K4me3","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus functional YTHDF2 rescue, single lab, multiple orthogonal methods","pmids":["35094011"],"is_preprint":false},{"year":2012,"finding":"Ifit2 is required for protection against lethal VSV neuropathogenesis following intranasal infection in mice. Ifit2−/− mice show several-hundred-fold higher VSV titers in the brain (without broadened cell tropism) compared to wild-type or Ifit1−/− mice, establishing Ifit2 as a tissue- and virus-specific ISG antiviral effector in the CNS.","method":"Ifit2−/− and Ifit1−/− knockout mouse infection models (intranasal VSV), viral titer quantification in CNS and peripheral organs, neurological phenotyping","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with specific antiviral phenotype; replicated across multiple tissues and virus doses with genetic comparisons","pmids":["22615570"],"is_preprint":false},{"year":2014,"finding":"Ifit2 protects peripheral nervous system neurons from VSV infection after subcutaneous footpad injection. In Ifit2−/− mice, VSV spread from lymph node to sciatic nerve, spinal cord, and brain causing paralysis, whereas in wild-type mice this neuronal spread was blocked despite equivalent viral replication in the lymph node.","method":"Ifit2−/− mouse model, subcutaneous footpad VSV injection, viral titer in lymph node, sciatic nerve, spinal cord, and brain, neurological outcome assessment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with precise anatomical dissection of tissue-specific antiviral function, replicated with multiple dose groups","pmids":["24991014"],"is_preprint":false},{"year":2017,"finding":"PLZF increases STAT1 protein levels, which drives IFIT2 mRNA transcription; ablation of IFIT2 in PLZF-overexpressing gallbladder cancer cells partially abrogates the tumor-suppressive effect of PLZF (reduced growth, EMT inhibition), placing IFIT2 downstream of PLZF/STAT1 in a growth-suppressive pathway.","method":"PLZF overexpression, IFIT2 shRNA knockdown in PLZF-OE cells (epistasis), STAT1 western blot, RT-PCR, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with rescue experiment and in vivo xenograft, single lab","pmids":["29358655"],"is_preprint":false},{"year":1996,"finding":"GARG-39 (murine IFIT2 homolog) was identified as a protein containing 10 tetratricopeptide repeat (TPR) domains, induced by LPS and interferons (α/β and γ) in macrophages. The TPR domain architecture was predicted to mediate protein-protein interactions in multicomponent assemblies.","method":"cDNA cloning, sequence analysis of TPR domains, northern blot induction assays in 3T3 cells and macrophages with LPS/IFN stimulation","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — molecular identification with structural domain analysis and expression characterization; foundational but primarily sequence/expression-based","pmids":["8660659"],"is_preprint":false},{"year":2024,"finding":"IFIT2 knockdown in foamy macrophages attenuates ox-LDL-induced iron retention (reduces ferritin-L, ferritin-H, Fe2+ and Fe3+) and promotes cholesterol efflux via upregulation of PPARγ/LXRα/ABCA1/ABCG1 pathway; in vivo Ifit2 knockdown in atherosclerotic APOE−/− mice reduces plaque area and lipid accumulation.","method":"shRNA lentivirus knockdown in HFD-induced APOE−/− mice (in vivo), ox-LDL-induced foamy macrophage model (in vitro), western blot for iron/cholesterol efflux proteins, iron measurement","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined pathway readout, single lab","pmids":["39276454"],"is_preprint":false},{"year":2020,"finding":"IFIT2 overexpression in K562 chronic myeloid leukemia cells inhibits cell proliferation and causes G1 arrest by inhibiting the BCR-ABL oncoprotein and its downstream AKT/mTOR signaling, and by inducing p27kip1 via degradation of cullin1-mediated E3 ligases.","method":"Stable IFIT2-overexpressing K562 cell line, cell cycle analysis, western blot for BCR-ABL, p-AKT, p-mTOR, p27kip1, and cullin1","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression only, western blot-based pathway inference without direct mechanistic reconstitution","pmids":["32124954"],"is_preprint":false},{"year":2025,"finding":"IRF1 directly binds to the IFIT2 gene promoter and activates its transcription, as validated by promoter-reporter (luciferase) assay and protein-binding microarray mapping of IRF1 binding motifs.","method":"Luciferase reporter assay with IFIT2 promoter constructs, protein-binding microarray, IRF1 knockout and overexpression in HeLa cells, RNA-seq","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay and microarray in single preprint, functional validation limited","pmids":[],"is_preprint":true},{"year":2024,"finding":"Biophysical characterization shows that cap-adjacent m6Am modification on RNA strongly blocks formation of the IFIT protein complex with RNA; the IFIT2-IFIT3 interaction (and IFIT1-IFIT3 interaction at nanomolar affinity) was characterized with kinetic parameters. m6A within the 5'UTR (not at cap) is not recognized by IFIT proteins and does not contribute to translation repression.","method":"Biophysical binding assays (SPR/ITC-type kinetics), RNA with defined 5'-cap modifications, IFIT protein complex reconstitution","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 2 / Weak — rigorous biophysical methods but preprint, single lab, awaiting peer review","pmids":[],"is_preprint":true}],"current_model":"IFIT2 is an interferon-stimulated RNA-binding protein that forms a domain-swapped heterodimer with IFIT3 (cryo-EM structure resolved at 3.2 Å); this IFIT2-IFIT3 complex recognizes short viral mRNA 5' UTRs (<50 nt) as a non-self molecular pattern and inhibits their translation, while IFIT2 also binds AU-rich mRNAs to prevent ribosome pausing and enhance translational efficiency—an activity exploited by influenza virus; downstream of interferon signaling, IFIT2 expression is driven by an IKKε→STAT1(Ser708) axis and its mRNA is subject to METTL3/YTHDF2-dependent m6A degradation; IFIT2 additionally functions as a microtubule-associated protein, promotes IFN-β/IRF3 signaling in macrophages, suppresses NADPH oxidase by binding p67phox, and acts as a tumor suppressor by restraining aPKC-mediated EMT, with its RNA-binding activity being essential for in vivo neuroprotection against neurotropic RNA viruses."},"narrative":{"mechanistic_narrative":"IFIT2 is an interferon-stimulated tetratricopeptide-repeat (TPR) protein that acts as an RNA-binding antiviral effector and immune signaling regulator [PMID:8660659, PMID:38888342]. It forms a domain-swapped heterodimer with IFIT3 that recognizes viral mRNAs bearing short 5' UTRs (<50 nucleotides) as a non-self molecular pattern, binding such RNAs and inhibiting their translation to confer antiviral activity against viruses including VSV and parainfluenza virus 3; the 5' UTR length requirement is necessary and sufficient and operates independently of cap structure [PMID:41093992, PMID:40079162]. Within the broader IFIT system, IFIT3 stabilizes IFIT1 and promotes its cap0 mRNA binding, and IFIT2–IFIT3 heterodimers form preferentially over homodimers and can further associate with IFIT1 [PMID:29554348]. Beyond restricting viral mRNAs, IFIT2 binds AU-rich regions of cellular and viral transcripts and prevents ribosome pausing to enhance translational efficiency, an activity that influenza virus repurposes to promote its own replication [PMID:32839537]. This RNA-binding activity is essential in vivo: an RNA-binding-deficient IFIT2 knock-in fails to protect mice from intranasal VSV, and IFIT2 acts specifically in neurons to block VSV neuropathogenesis through both peripheral-nerve and CNS routes [PMID:38888342, PMID:22615570, PMID:24991014]. IFIT2 expression is driven downstream of interferon signaling via an IKKε→STAT1(Ser708) axis and through STAT1-dependent transcription, and its mRNA is destabilized by METTL3/YTHDF2-dependent m6A decay [PMID:22065572, PMID:35094011]. IFIT2 additionally functions as a microtubule-associated protein enriched in the mitotic spindle [PMID:17030862], amplifies IFN-β/IRF3 signaling and inflammatory cytokine output in macrophages [PMID:24014876, PMID:24198415], suppresses NADPH oxidase by binding the p67phox subunit [PMID:29666281], and acts as a tumor suppressor by restraining aPKC-mediated epithelial-mesenchymal transition [PMID:22986528, PMID:29358655].","teleology":[{"year":1996,"claim":"Established the molecular identity of IFIT2 as an interferon- and LPS-inducible protein built from tetratricopeptide repeats, framing it from the outset as a scaffold for protein-protein interactions.","evidence":"cDNA cloning, TPR sequence analysis, and northern blot induction in macrophages and 3T3 cells (murine GARG-39 homolog)","pmids":["8660659"],"confidence":"Medium","gaps":["No biochemical demonstration of any binding partner at this stage","No functional antiviral or signaling assay"]},{"year":2006,"claim":"Showed IFIT2 has a cytoskeletal role independent of RNA biology, binding microtubules and localizing to the mitotic spindle.","evidence":"In vitro microtubule binding assay and immunofluorescence co-localization with β-tubulin","pmids":["17030862"],"confidence":"Medium","gaps":["Functional consequence for mitosis not established","Relationship to RNA-binding function unclear"]},{"year":2008,"claim":"Defined a post-transcriptional immunomodulatory function whereby IFIT2 dampens inflammatory cytokine output by reducing mRNA stability.","evidence":"IFIT2-overexpressing RAW264.7 macrophages with actinomycin D mRNA stability chase and cytokine ELISA","pmids":["19108715"],"confidence":"Medium","gaps":["Direct RNA binding not demonstrated here","3' UTR determinants of susceptibility not defined at sequence level","Overexpression-based, no loss-of-function"]},{"year":2011,"claim":"Placed IFIT2 induction within a specific signaling axis, identifying IKKε-driven STAT1 Ser708 phosphorylation as required for IFIT2 expression and antiviral control of WNV.","evidence":"IKKε−/− and IFIT2−/− models, site-specific STAT1 phosphorylation analysis, CRM1 inhibition, WNV infection","pmids":["22065572"],"confidence":"Medium","gaps":["Direct kinase-substrate biochemistry between IKKε and STAT1 Ser708 not reconstituted","Generality beyond WNV not tested"]},{"year":2012,"claim":"Established IFIT2 as a tissue- and virus-specific antiviral effector in the CNS and as a tumor suppressor restraining EMT, revealing two distinct disease-relevant roles.","evidence":"Intranasal VSV challenge of Ifit2−/− vs Ifit1−/− mice; IFIT2 shRNA knockdown and aPKC epistasis in oral squamous carcinoma cells with metastasis model","pmids":["22615570","22986528"],"confidence":"High","gaps":["Molecular basis of CNS-specific protection not defined at this stage","Mechanism linking IFIT2 loss to aPKC activation unresolved"]},{"year":2013,"claim":"Distinguished IFIT2 as a positive regulator of interferon induction and inflammatory signaling, not merely a direct effector, by showing it promotes IFN-α/β and IRF3 activation in macrophages.","evidence":"Ifit2−/− macrophages with MHV coronavirus and LPS endotoxin models, IRF3 phosphorylation western blot, cytokine ELISA","pmids":["24198415","24014876"],"confidence":"Medium","gaps":["Mechanism by which IFIT2 promotes IRF3 phosphorylation unknown","No direct molecular partner identified in this signaling step"]},{"year":2014,"claim":"Mapped IFIT2 antiviral protection to neuronal compartments by tracing blocked VSV spread from periphery to CNS in knockout mice.","evidence":"Subcutaneous footpad VSV infection of Ifit2−/− mice with anatomical viral titer dissection","pmids":["24991014"],"confidence":"High","gaps":["Molecular mechanism of neuronal protection not yet established","Cell-intrinsic vs systemic contribution not resolved"]},{"year":2016,"claim":"Connected IFIT2 transcription to JAK-STAT pathway integrity, showing AJUBA-mediated JAK1 dissociation represses STAT1-dependent IFIT2 expression and apoptosis in cancer.","evidence":"Co-IP of AJUBA-JAK1, STAT1 phosphorylation and IFIT2 expression analysis, apoptosis assays in colorectal cancer cells","pmids":["27893714"],"confidence":"Medium","gaps":["IFIT2's direct contribution to apoptosis not isolated from broader STAT1 program","Single-lab Co-IP"]},{"year":2017,"claim":"Reinforced IFIT2's tumor-suppressive role as a downstream effector of the PLZF/STAT1 growth-suppressive axis, and revealed its proteasome-coupled centrosomal aggregation behavior.","evidence":"PLZF overexpression with IFIT2 knockdown epistasis and xenograft; proteasome inhibition with colchicine/ciliobrevin perturbation of IFIT2 localization and apoptosis assay","pmids":["29358655","28367102"],"confidence":"Medium","gaps":["Mechanism linking IFIT2 to growth suppression downstream of STAT1 incomplete","Functional role of centrosomal aggregation unclear"]},{"year":2018,"claim":"Resolved the architecture of the IFIT complex, showing IFIT2-IFIT3 heterodimers form preferentially and that IFIT3 stabilizes IFIT1 and enhances its translation-inhibitory activity, and identified IFIT2 as a p67phox-binding suppressor of NADPH oxidase.","evidence":"In vitro reconstitution of IFIT complexes with YxxxL mutagenesis and cap0 mRNA assays; Co-IP and ROS measurement in Ifit2-knockout leukocytes with C. albicans model","pmids":["29554348","29666281"],"confidence":"Medium","gaps":["Structural basis of heterodimer formation not yet resolved at this stage","Mechanism of p67phox suppression beyond binding not defined"]},{"year":2020,"claim":"Defined IFIT2's RNA-binding specificity and dual translational role, showing it binds AU-rich mRNAs to prevent ribosome pausing and enhance translation—an activity hijacked by influenza.","evidence":"CLIP-seq, polysome and ribosome profiling, and CRISPR-Cas9 knockout during influenza infection","pmids":["32839537"],"confidence":"High","gaps":["Reconciliation of translation enhancement with translation inhibition of short-UTR viral mRNAs not fully mechanistic","Structural basis of AU-rich recognition not resolved here"]},{"year":2022,"claim":"Identified an m6A-based decay mechanism controlling IFIT2 abundance, linking METTL3/YTHDF2 to destabilization of IFIT2 mRNA in cancer.","evidence":"METTL3 perturbation, MeRIP-seq, YTHDF2 rescue, and mRNA stability assays in intrahepatic cholangiocarcinoma","pmids":["35094011"],"confidence":"Medium","gaps":["Generality of m6A control of IFIT2 across cell types untested","Single-lab"]},{"year":2024,"claim":"Provided definitive in vivo evidence that RNA binding is the essential antiviral activity of IFIT2 and that it acts cell-autonomously in neurons.","evidence":"RNA-binding mutant knock-in and neuron-specific conditional knockout mice challenged with VSV","pmids":["38888342"],"confidence":"High","gaps":["Identity of the in vivo RNA targets driving protection not enumerated","Contribution of IFIT3 partnership in neurons not tested"]},{"year":2025,"claim":"Delivered the structural basis for IFIT2-IFIT3 antiviral recognition, showing a domain-swapped heterodimer that reads short 5' UTRs as a self/non-self discriminator independent of cap structure.","evidence":"3.2 Å cryo-EM structure, in vitro translation inhibition, RNA binding to VEEV UTRs, and 5' UTR length-swap reporters","pmids":["41093992","40079162"],"confidence":"High","gaps":["How short-UTR recognition is reconciled with AU-rich translation enhancement remains open","In vivo relevance of the structural mechanism to neuronal protection not directly linked"]},{"year":null,"claim":"It remains unresolved how IFIT2's opposing translational activities—repression of short-UTR viral mRNAs within the IFIT2-IFIT3 complex versus enhancement of AU-rich mRNA translation—are mechanistically partitioned and regulated in vivo, and which RNA targets underlie its neuron-specific protection.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating translation-enhancing and translation-repressing activities","In vivo RNA targets in neurons not identified","Role of microtubule association relative to RNA functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9,10,15]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,15,16]}],"complexes":["IFIT2-IFIT3 heterodimer"],"partners":["IFIT3","IFIT1","P67PHOX","TUBB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09913","full_name":"Interferon-induced protein with tetratricopeptide repeats 2","aliases":["ISG-54 K","Interferon-induced 54 kDa protein","IFI-54K","P54"],"length_aa":472,"mass_kda":54.6,"function":"IFN-induced antiviral protein which inhibits expression of viral messenger RNAs lacking 2'-O-methylation of the 5' cap. The ribose 2'-O-methylation would provide a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Viruses evolved several ways to evade this restriction system such as encoding their own 2'-O-methylase for their mRNAs or by stealing host cap containing the 2'-O-methylation (cap snatching mechanism). Binds AU-rich viral RNAs, with or without 5' triphosphorylation, RNA-binding is required for antiviral activity. Can promote apoptosis","subcellular_location":"Cytoplasm; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P09913/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFIT2","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/IFIT2","total_profiled":1310},"omim":[{"mim_id":"604650","title":"INTERFERON-INDUCED PROTEIN WITH TETRATRICOPEPTIDE REPEATS 3; IFIT3","url":"https://www.omim.org/entry/604650"},{"mim_id":"600664","title":"COMPONENT OF NUCLEAR FACTOR KAPPA-B KINASE COMPLEX; CHUK","url":"https://www.omim.org/entry/600664"},{"mim_id":"147040","title":"INTERFERON-INDUCED PROTEIN WITH TETRATRICOPEPTIDE REPEATS 2; IFIT2","url":"https://www.omim.org/entry/147040"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone 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virus 3.\",\n      \"method\": \"Cryo-EM structure determination (3.2 Å), in vitro translation inhibition assays, antiviral activity assays with recombinant viruses, 5' UTR length-swap reporter experiments\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure at 3.2 Å combined with functional translation inhibition and antiviral assays; independently supported by preprint (bio_10.1101_2025.02.11.637299) using same methods\",\n      \"pmids\": [\"41093992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFIT2-IFIT3 heterodimer binds directly to the VEEV 3' UTR in vitro; 5' UTR lengths <50 nucleotides are necessary and sufficient for translation inhibition by the IFIT2-IFIT3 complex, independent of cap structure.\",\n      \"method\": \"In vitro RNA-binding assays, recombinant VEEV clones with swapped 3' UTRs, in vitro translation inhibition assays\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus viral infection experiments in single study, consistent with structural data from PMID 41093992\",\n      \"pmids\": [\"40079162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFIT1 and IFIT3 interact via a YxxxL motif in their C-termini; IFIT2 and IFIT3 form homodimers that dissociate to yield a more stable IFIT2-IFIT3 heterodimer, which also associates with IFIT1. IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to cap0 Zika virus reporter mRNA, and enhances IFIT1-mediated translation inhibition.\",\n      \"method\": \"In vitro reconstitution of IFIT complexes, cap0 mRNA-binding assay, translation inhibition assay, site-directed mutagenesis of YxxxL motif\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis and multiple functional readouts in a single rigorous study\",\n      \"pmids\": [\"29554348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFIT2 binds directly to viral and cellular mRNAs in AU-rich regions (demonstrated by CLIP-seq during influenza virus infection); ribosome/polysome profiling showed that IFIT2 prevents ribosome pausing on bound mRNAs, thereby enhancing translational efficiency. Influenza virus repurposes this activity to promote viral mRNA translation and replication.\",\n      \"method\": \"CLIP-seq, polysome profiling, ribosome profiling, CRISPR-Cas9 knockout screen\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal transcriptomic methods (CLIP-seq, polysome and ribosome profiling) with functional CRISPR validation in a single rigorous study\",\n      \"pmids\": [\"32839537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFIT2 RNA-binding activity is essential for its antiviral function in vivo: mice expressing a mutant IFIT2 that cannot bind RNA were as susceptible to intranasal VSV infection as Ifit2−/− mice. Additionally, neuron-specific conditional knockout of Ifit2 was sufficient to render mice susceptible to VSV neuropathogenesis via the intranasal (but not subcutaneous) route, placing IFIT2 function specifically in neurons.\",\n      \"method\": \"Conditional knockout mouse (neuron-specific Cre), RNA-binding mutant knock-in mouse, intranasal/subcutaneous VSV challenge, survival and viral load analysis\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent genetically modified mouse lines with functional in vivo readouts, loss-of-function with specific mechanistic test (RNA-binding mutant)\",\n      \"pmids\": [\"38888342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GARG39/IFIT2 protein interacts with microtubules in vitro, co-localizes with β-tubulin in vivo, and is enriched in the mitotic spindle of non-neuronal cells undergoing mitosis, identifying it as a microtubule-associated protein.\",\n      \"method\": \"In vitro microtubule binding assay, immunofluorescence co-localization with β-tubulin, mitotic cell imaging\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assay combined with immunofluorescence co-localization, single lab\",\n      \"pmids\": [\"17030862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Proteasome inhibition blocks IFIT2 degradation and causes IFIT2 to aggregate at the centrosome; this aggregation depends on intact microtubule dynamics (colchicine-sensitive) and dynein activity (ciliobrevin-sensitive). IFIT2 combined with proteasome inhibitor synergistically induces cancer cell apoptosis.\",\n      \"method\": \"Immunofluorescence localization after proteasome inhibitor treatment, pharmacological inhibition of microtubules (colchicine) and dynein (ciliobrevin), apoptosis assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with pharmacological perturbations and functional apoptosis readout, single lab\",\n      \"pmids\": [\"28367102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFIT2 is a binding partner of p67phox, a critical regulatory subunit of NADPH oxidase; loss of IFIT2 increases ROS production by leukocytes, suggesting IFIT2 suppresses NADPH oxidase activation. Ifit2 knockout mice showed improved survival and reduced fungal burden in a systemic Candida albicans model.\",\n      \"method\": \"Co-immunoprecipitation/binding partner identification, ROS measurement in Ifit2-knockout leukocytes, in vivo C. albicans infection survival study\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding identified plus functional leukocyte assay in KO mice, single lab, two orthogonal methods\",\n      \"pmids\": [\"29666281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ifit2 deficiency in macrophages impairs IFN-α/β mRNA and protein production following MHV coronavirus infection, placing Ifit2 as a positive regulator of IFN-α/β induction (rather than solely a direct antiviral effector) in macrophages during coronavirus CNS infection.\",\n      \"method\": \"Ifit2−/− mouse model, ex vivo microglia/macrophage analysis, IFN-α/β mRNA and protein quantification in bone marrow-derived macrophages, in vivo viral load measurement\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO model with defined cellular phenotype and IFN measurement, single lab\",\n      \"pmids\": [\"24198415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IKKε phosphorylates STAT1 at serine 708, which is required for IFIT2 expression; loss of IKKε abrogates IFIT2 induction and enhances WNV replication. STAT1 tyrosine dephosphorylation and CRM1-mediated nuclear-cytoplasmic shuttling are prerequisites for Ser-708 phosphorylation. This defines an IFN-induced IKKε→STAT1(Ser708)→IFIT2 signaling axis.\",\n      \"method\": \"IKKε−/− and IFIT2−/− cell/mouse models, STAT1 phosphorylation analysis (site-specific antibodies), CRM1 inhibitor (leptomycin B) treatment, WNV infection assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with multiple genetic KO models and biochemical phosphorylation analysis, single lab\",\n      \"pmids\": [\"22065572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFIT2 promotes IRF3 phosphorylation, thereby amplifying LPS-induced IFN-β production and subsequent IL-6/TNF-α secretion (post-transcriptionally). Ifit2-deficient mice show reduced serum IL-6 and TNF-α and reduced mortality in endotoxin shock. IFIT2 expression is induced in an IFN-α receptor- and IRF9-dependent manner.\",\n      \"method\": \"Ifit2−/− mouse generation, bone marrow-derived macrophage cytokine assays (ELISA), IRF3 phosphorylation western blotting, LPS endotoxin shock model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined signaling readout (IRF3 phosphorylation) and in vivo phenotype, single lab\",\n      \"pmids\": [\"24014876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Overexpression of IFIT2 in macrophages selectively reduces LPS-induced TNF-α, IL-6, and MIP-2 expression by decreasing mRNA stability at the post-transcriptional level; characteristics of the 3' UTR of transcripts determine susceptibility to IFIT2-mediated regulation.\",\n      \"method\": \"Stable IFIT2-overexpressing RAW264.7 macrophage lines, mRNA stability assay (actinomycin D chase), ELISA, western blot\",\n      \"journal\": \"BMC immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with mRNA stability mechanistic assay, single lab, two orthogonal readouts\",\n      \"pmids\": [\"19108715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Depletion of IFIT2 in oral squamous cell carcinoma cells activates atypical PKC (aPKC), leading to epithelial-mesenchymal transition, enhanced cell migration, and invasiveness. Inhibition of aPKC (by pseudosubstrate or siRNA) abolished these phenotypes, placing aPKC downstream of IFIT2.\",\n      \"method\": \"Stable IFIT2 shRNA knockdown cell lines, aPKC pseudosubstrate inhibitor treatment, siRNA knockdown of aPKC, migration/invasion assays, tail-vein metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via chemical and genetic inhibition of aPKC, with functional rescue, single lab\",\n      \"pmids\": [\"22986528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AJUBA binds directly to the FERM domain of JAK1, dissociating JAK1 from the IFN-γ receptor and thereby inhibiting STAT1 phosphorylation and nuclear translocation, which represses IFIT2 gene expression and inhibits apoptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (AJUBA-JAK1 binding), STAT1 phosphorylation assay, IFIT2 promoter/expression analysis, apoptosis assays, siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying direct binding partner combined with functional STAT1→IFIT2 pathway dissection, single lab\",\n      \"pmids\": [\"27893714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3 mediates m6A modification of IFIT2 mRNA, which accelerates IFIT2 mRNA decay in a YTHDF2-dependent manner in intrahepatic cholangiocarcinoma. METTL3 transcription itself is driven by H3K4me3 activation.\",\n      \"method\": \"METTL3 knockdown/overexpression, MeRIP-seq (m6A mapping), YTHDF2 knockdown rescue experiments, mRNA stability assays, ChIP-seq for H3K4me3\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus functional YTHDF2 rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35094011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ifit2 is required for protection against lethal VSV neuropathogenesis following intranasal infection in mice. Ifit2−/− mice show several-hundred-fold higher VSV titers in the brain (without broadened cell tropism) compared to wild-type or Ifit1−/− mice, establishing Ifit2 as a tissue- and virus-specific ISG antiviral effector in the CNS.\",\n      \"method\": \"Ifit2−/− and Ifit1−/− knockout mouse infection models (intranasal VSV), viral titer quantification in CNS and peripheral organs, neurological phenotyping\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with specific antiviral phenotype; replicated across multiple tissues and virus doses with genetic comparisons\",\n      \"pmids\": [\"22615570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ifit2 protects peripheral nervous system neurons from VSV infection after subcutaneous footpad injection. In Ifit2−/− mice, VSV spread from lymph node to sciatic nerve, spinal cord, and brain causing paralysis, whereas in wild-type mice this neuronal spread was blocked despite equivalent viral replication in the lymph node.\",\n      \"method\": \"Ifit2−/− mouse model, subcutaneous footpad VSV injection, viral titer in lymph node, sciatic nerve, spinal cord, and brain, neurological outcome assessment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with precise anatomical dissection of tissue-specific antiviral function, replicated with multiple dose groups\",\n      \"pmids\": [\"24991014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PLZF increases STAT1 protein levels, which drives IFIT2 mRNA transcription; ablation of IFIT2 in PLZF-overexpressing gallbladder cancer cells partially abrogates the tumor-suppressive effect of PLZF (reduced growth, EMT inhibition), placing IFIT2 downstream of PLZF/STAT1 in a growth-suppressive pathway.\",\n      \"method\": \"PLZF overexpression, IFIT2 shRNA knockdown in PLZF-OE cells (epistasis), STAT1 western blot, RT-PCR, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with rescue experiment and in vivo xenograft, single lab\",\n      \"pmids\": [\"29358655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"GARG-39 (murine IFIT2 homolog) was identified as a protein containing 10 tetratricopeptide repeat (TPR) domains, induced by LPS and interferons (α/β and γ) in macrophages. The TPR domain architecture was predicted to mediate protein-protein interactions in multicomponent assemblies.\",\n      \"method\": \"cDNA cloning, sequence analysis of TPR domains, northern blot induction assays in 3T3 cells and macrophages with LPS/IFN stimulation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — molecular identification with structural domain analysis and expression characterization; foundational but primarily sequence/expression-based\",\n      \"pmids\": [\"8660659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFIT2 knockdown in foamy macrophages attenuates ox-LDL-induced iron retention (reduces ferritin-L, ferritin-H, Fe2+ and Fe3+) and promotes cholesterol efflux via upregulation of PPARγ/LXRα/ABCA1/ABCG1 pathway; in vivo Ifit2 knockdown in atherosclerotic APOE−/− mice reduces plaque area and lipid accumulation.\",\n      \"method\": \"shRNA lentivirus knockdown in HFD-induced APOE−/− mice (in vivo), ox-LDL-induced foamy macrophage model (in vitro), western blot for iron/cholesterol efflux proteins, iron measurement\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined pathway readout, single lab\",\n      \"pmids\": [\"39276454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFIT2 overexpression in K562 chronic myeloid leukemia cells inhibits cell proliferation and causes G1 arrest by inhibiting the BCR-ABL oncoprotein and its downstream AKT/mTOR signaling, and by inducing p27kip1 via degradation of cullin1-mediated E3 ligases.\",\n      \"method\": \"Stable IFIT2-overexpressing K562 cell line, cell cycle analysis, western blot for BCR-ABL, p-AKT, p-mTOR, p27kip1, and cullin1\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression only, western blot-based pathway inference without direct mechanistic reconstitution\",\n      \"pmids\": [\"32124954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRF1 directly binds to the IFIT2 gene promoter and activates its transcription, as validated by promoter-reporter (luciferase) assay and protein-binding microarray mapping of IRF1 binding motifs.\",\n      \"method\": \"Luciferase reporter assay with IFIT2 promoter constructs, protein-binding microarray, IRF1 knockout and overexpression in HeLa cells, RNA-seq\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay and microarray in single preprint, functional validation limited\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biophysical characterization shows that cap-adjacent m6Am modification on RNA strongly blocks formation of the IFIT protein complex with RNA; the IFIT2-IFIT3 interaction (and IFIT1-IFIT3 interaction at nanomolar affinity) was characterized with kinetic parameters. m6A within the 5'UTR (not at cap) is not recognized by IFIT proteins and does not contribute to translation repression.\",\n      \"method\": \"Biophysical binding assays (SPR/ITC-type kinetics), RNA with defined 5'-cap modifications, IFIT protein complex reconstitution\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — rigorous biophysical methods but preprint, single lab, awaiting peer review\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IFIT2 is an interferon-stimulated RNA-binding protein that forms a domain-swapped heterodimer with IFIT3 (cryo-EM structure resolved at 3.2 Å); this IFIT2-IFIT3 complex recognizes short viral mRNA 5' UTRs (<50 nt) as a non-self molecular pattern and inhibits their translation, while IFIT2 also binds AU-rich mRNAs to prevent ribosome pausing and enhance translational efficiency—an activity exploited by influenza virus; downstream of interferon signaling, IFIT2 expression is driven by an IKKε→STAT1(Ser708) axis and its mRNA is subject to METTL3/YTHDF2-dependent m6A degradation; IFIT2 additionally functions as a microtubule-associated protein, promotes IFN-β/IRF3 signaling in macrophages, suppresses NADPH oxidase by binding p67phox, and acts as a tumor suppressor by restraining aPKC-mediated EMT, with its RNA-binding activity being essential for in vivo neuroprotection against neurotropic RNA viruses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFIT2 is an interferon-stimulated tetratricopeptide-repeat (TPR) protein that acts as an RNA-binding antiviral effector and immune signaling regulator [#18, #4]. It forms a domain-swapped heterodimer with IFIT3 that recognizes viral mRNAs bearing short 5' UTRs (<50 nucleotides) as a non-self molecular pattern, binding such RNAs and inhibiting their translation to confer antiviral activity against viruses including VSV and parainfluenza virus 3; the 5' UTR length requirement is necessary and sufficient and operates independently of cap structure [#0, #1]. Within the broader IFIT system, IFIT3 stabilizes IFIT1 and promotes its cap0 mRNA binding, and IFIT2–IFIT3 heterodimers form preferentially over homodimers and can further associate with IFIT1 [#2]. Beyond restricting viral mRNAs, IFIT2 binds AU-rich regions of cellular and viral transcripts and prevents ribosome pausing to enhance translational efficiency, an activity that influenza virus repurposes to promote its own replication [#3]. This RNA-binding activity is essential in vivo: an RNA-binding-deficient IFIT2 knock-in fails to protect mice from intranasal VSV, and IFIT2 acts specifically in neurons to block VSV neuropathogenesis through both peripheral-nerve and CNS routes [#4, #15, #16]. IFIT2 expression is driven downstream of interferon signaling via an IKKε→STAT1(Ser708) axis and through STAT1-dependent transcription, and its mRNA is destabilized by METTL3/YTHDF2-dependent m6A decay [#9, #14]. IFIT2 additionally functions as a microtubule-associated protein enriched in the mitotic spindle [#5], amplifies IFN-β/IRF3 signaling and inflammatory cytokine output in macrophages [#10, #8], suppresses NADPH oxidase by binding the p67phox subunit [#7], and acts as a tumor suppressor by restraining aPKC-mediated epithelial-mesenchymal transition [#12, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of IFIT2 as an interferon- and LPS-inducible protein built from tetratricopeptide repeats, framing it from the outset as a scaffold for protein-protein interactions.\",\n      \"evidence\": \"cDNA cloning, TPR sequence analysis, and northern blot induction in macrophages and 3T3 cells (murine GARG-39 homolog)\",\n      \"pmids\": [\"8660659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical demonstration of any binding partner at this stage\", \"No functional antiviral or signaling assay\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed IFIT2 has a cytoskeletal role independent of RNA biology, binding microtubules and localizing to the mitotic spindle.\",\n      \"evidence\": \"In vitro microtubule binding assay and immunofluorescence co-localization with β-tubulin\",\n      \"pmids\": [\"17030862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for mitosis not established\", \"Relationship to RNA-binding function unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a post-transcriptional immunomodulatory function whereby IFIT2 dampens inflammatory cytokine output by reducing mRNA stability.\",\n      \"evidence\": \"IFIT2-overexpressing RAW264.7 macrophages with actinomycin D mRNA stability chase and cytokine ELISA\",\n      \"pmids\": [\"19108715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA binding not demonstrated here\", \"3' UTR determinants of susceptibility not defined at sequence level\", \"Overexpression-based, no loss-of-function\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed IFIT2 induction within a specific signaling axis, identifying IKKε-driven STAT1 Ser708 phosphorylation as required for IFIT2 expression and antiviral control of WNV.\",\n      \"evidence\": \"IKKε−/− and IFIT2−/− models, site-specific STAT1 phosphorylation analysis, CRM1 inhibition, WNV infection\",\n      \"pmids\": [\"22065572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase-substrate biochemistry between IKKε and STAT1 Ser708 not reconstituted\", \"Generality beyond WNV not tested\"]\n    },\n    {\n      \"year\": \"2012\",\n      \"claim\": \"Established IFIT2 as a tissue- and virus-specific antiviral effector in the CNS and as a tumor suppressor restraining EMT, revealing two distinct disease-relevant roles.\",\n      \"evidence\": \"Intranasal VSV challenge of Ifit2−/− vs Ifit1−/− mice; IFIT2 shRNA knockdown and aPKC epistasis in oral squamous carcinoma cells with metastasis model\",\n      \"pmids\": [\"22615570\", \"22986528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of CNS-specific protection not defined at this stage\", \"Mechanism linking IFIT2 loss to aPKC activation unresolved\"]\n    },\n    {\n      \"year\": \"2013\",\n      \"claim\": \"Distinguished IFIT2 as a positive regulator of interferon induction and inflammatory signaling, not merely a direct effector, by showing it promotes IFN-α/β and IRF3 activation in macrophages.\",\n      \"evidence\": \"Ifit2−/− macrophages with MHV coronavirus and LPS endotoxin models, IRF3 phosphorylation western blot, cytokine ELISA\",\n      \"pmids\": [\"24198415\", \"24014876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IFIT2 promotes IRF3 phosphorylation unknown\", \"No direct molecular partner identified in this signaling step\"]\n    },\n    {\n      \"year\": \"2014\",\n      \"claim\": \"Mapped IFIT2 antiviral protection to neuronal compartments by tracing blocked VSV spread from periphery to CNS in knockout mice.\",\n      \"evidence\": \"Subcutaneous footpad VSV infection of Ifit2−/− mice with anatomical viral titer dissection\",\n      \"pmids\": [\"24991014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of neuronal protection not yet established\", \"Cell-intrinsic vs systemic contribution not resolved\"]\n    },\n    {\n      \"year\": \"2016\",\n      \"claim\": \"Connected IFIT2 transcription to JAK-STAT pathway integrity, showing AJUBA-mediated JAK1 dissociation represses STAT1-dependent IFIT2 expression and apoptosis in cancer.\",\n      \"evidence\": \"Co-IP of AJUBA-JAK1, STAT1 phosphorylation and IFIT2 expression analysis, apoptosis assays in colorectal cancer cells\",\n      \"pmids\": [\"27893714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IFIT2's direct contribution to apoptosis not isolated from broader STAT1 program\", \"Single-lab Co-IP\"]\n    },\n    {\n      \"year\": \"2017\",\n      \"claim\": \"Reinforced IFIT2's tumor-suppressive role as a downstream effector of the PLZF/STAT1 growth-suppressive axis, and revealed its proteasome-coupled centrosomal aggregation behavior.\",\n      \"evidence\": \"PLZF overexpression with IFIT2 knockdown epistasis and xenograft; proteasome inhibition with colchicine/ciliobrevin perturbation of IFIT2 localization and apoptosis assay\",\n      \"pmids\": [\"29358655\", \"28367102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking IFIT2 to growth suppression downstream of STAT1 incomplete\", \"Functional role of centrosomal aggregation unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the architecture of the IFIT complex, showing IFIT2-IFIT3 heterodimers form preferentially and that IFIT3 stabilizes IFIT1 and enhances its translation-inhibitory activity, and identified IFIT2 as a p67phox-binding suppressor of NADPH oxidase.\",\n      \"evidence\": \"In vitro reconstitution of IFIT complexes with YxxxL mutagenesis and cap0 mRNA assays; Co-IP and ROS measurement in Ifit2-knockout leukocytes with C. albicans model\",\n      \"pmids\": [\"29554348\", \"29666281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of heterodimer formation not yet resolved at this stage\", \"Mechanism of p67phox suppression beyond binding not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined IFIT2's RNA-binding specificity and dual translational role, showing it binds AU-rich mRNAs to prevent ribosome pausing and enhance translation—an activity hijacked by influenza.\",\n      \"evidence\": \"CLIP-seq, polysome and ribosome profiling, and CRISPR-Cas9 knockout during influenza infection\",\n      \"pmids\": [\"32839537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of translation enhancement with translation inhibition of short-UTR viral mRNAs not fully mechanistic\", \"Structural basis of AU-rich recognition not resolved here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified an m6A-based decay mechanism controlling IFIT2 abundance, linking METTL3/YTHDF2 to destabilization of IFIT2 mRNA in cancer.\",\n      \"evidence\": \"METTL3 perturbation, MeRIP-seq, YTHDF2 rescue, and mRNA stability assays in intrahepatic cholangiocarcinoma\",\n      \"pmids\": [\"35094011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of m6A control of IFIT2 across cell types untested\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided definitive in vivo evidence that RNA binding is the essential antiviral activity of IFIT2 and that it acts cell-autonomously in neurons.\",\n      \"evidence\": \"RNA-binding mutant knock-in and neuron-specific conditional knockout mice challenged with VSV\",\n      \"pmids\": [\"38888342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the in vivo RNA targets driving protection not enumerated\", \"Contribution of IFIT3 partnership in neurons not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Delivered the structural basis for IFIT2-IFIT3 antiviral recognition, showing a domain-swapped heterodimer that reads short 5' UTRs as a self/non-self discriminator independent of cap structure.\",\n      \"evidence\": \"3.2 Å cryo-EM structure, in vitro translation inhibition, RNA binding to VEEV UTRs, and 5' UTR length-swap reporters\",\n      \"pmids\": [\"41093992\", \"40079162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How short-UTR recognition is reconciled with AU-rich translation enhancement remains open\", \"In vivo relevance of the structural mechanism to neuronal protection not directly linked\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how IFIT2's opposing translational activities—repression of short-UTR viral mRNAs within the IFIT2-IFIT3 complex versus enhancement of AU-rich mRNA translation—are mechanistically partitioned and regulated in vivo, and which RNA targets underlie its neuron-specific protection.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating translation-enhancing and translation-repressing activities\", \"In vivo RNA targets in neurons not identified\", \"Role of microtubule association relative to RNA functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9, 10, 15]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 15, 16]}\n    ],\n    \"complexes\": [\"IFIT2-IFIT3 heterodimer\"],\n    \"partners\": [\"IFIT3\", \"IFIT1\", \"p67phox\", \"TUBB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}