{"gene":"IFITM2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2015,"finding":"IFITM2 localizes to late endosomes and lysosomes in hepatocytes, and restricts HCV at the late entry stage; S-palmitoylation of IFITM2 is essential for anti-HCV activity, while a conserved N-terminal tyrosine residue governs protein localization but is dispensable for antiviral activity.","method":"Subcellular fractionation/colocalization imaging, site-directed mutagenesis of palmitoylation sites and tyrosine residue, antiviral entry assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, mutagenesis, functional assay) in a single well-cited study","pmids":["26354436"],"is_preprint":false},{"year":2013,"finding":"IFITM2 (and IFITM3, but not IFITM1) restricts Rift Valley fever virus primarily by preventing viral membrane fusion with endosomes, with no effect on virion attachment, endocytosis, or viral replication kinetics; IFITM2 occupies vesicular compartments distinct from those of IFITM1 and expands vesicular/acidified compartments when overexpressed.","method":"Overexpression and knockdown antiviral assays, entry step dissection (attachment, endocytosis, fusion assays), subcellular localization imaging","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods dissecting entry step with localization in a well-cited study","pmids":["23720721"],"is_preprint":false},{"year":2021,"finding":"IFITM2 is the predominant IFITM family member restricting SARS-CoV-2 replication; restriction is governed by route of viral entry, with the polybasic furin cleavage site in spike allowing pH-independent entry that partially evades IFITM2-mediated restriction; targeted depletion of IFITM2 alleviates type I IFN-mediated inhibition of SARS-CoV-2 replication.","method":"siRNA knockdown, pseudovirus and authentic SARS-CoV-2 infection assays, entry route pharmacological dissection, IFN treatment with IFITM2 depletion","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, entry pharmacology, pseudovirus/authentic virus) replicated across conditions","pmids":["33563656"],"is_preprint":false},{"year":2022,"finding":"IFITM2 acts as a proviral cofactor (hijacked by SARS-CoV-2) for efficient replication; depletion of endogenous IFITM2 in human lung cells reduces infectious virus production by all SARS-CoV-2 variants of concern by more than 4 orders of magnitude; an anti-IFITM2 N-terminal antibody inhibits VOC replication in iPSC-derived alveolar epithelial type II cells.","method":"siRNA knockdown, authentic SARS-CoV-2 VOC infection assays in Calu-3 cells and iPSC-derived cells, neutralizing antibody treatment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — replicated across five VOCs, multiple cell types, antibody validation","pmids":["35543509"],"is_preprint":false},{"year":2017,"finding":"A 20-amino-acid N-terminal truncation isoform of IFITM2 (Δ20 IFITM2) differentially restricts X4-tropic but not R5-tropic HIV-1 by inhibiting viral entry; coreceptor identity (CXCR4 vs CCR5 C-terminus) determines susceptibility to Δ20 IFITM2-mediated restriction; Δ20 IFITM2 is expressed in CD4+ T cells and monocytes.","method":"Overexpression and siRNA depletion in monocyte-derived macrophages and dendritic cells, chimeric coreceptor swap constructs, entry assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — isoform characterization with mechanistic chimera experiments and multiple cell types","pmids":["28630320"],"is_preprint":false},{"year":2009,"finding":"IFITM2 (1-8D) functions as a pro-apoptotic gene independent of p53; transient expression causes G1 arrest followed by apoptosis (confirmed by Annexin-V and TUNEL); apoptosis induction requires caspase activity; knockdown of IFITM2 provides partial protection from etoposide- and UV-induced apoptosis; p53 expression downregulates IFITM2 protein levels.","method":"Transient transfection in multiple mammalian cell lines, cell cycle analysis, Annexin-V binding, TUNEL assay, caspase inhibitor experiments, siRNA knockdown","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal apoptosis assays with gain- and loss-of-function in multiple cell lines","pmids":["19544527"],"is_preprint":false},{"year":2003,"finding":"IFITM2 (Inid/1-8D gene product) physically interacts with adenovirus precursor terminal protein (pTP), identified by yeast two-hybrid screen of HeLa cDNA library; expression of IFITM2 in adenovirus-infected cells induces apoptosis, suggesting the pTP-binding targets infected cells for apoptotic destruction as a host defense.","method":"Yeast two-hybrid screen, tetracycline-inducible expression, TdT assay, DNA fragmentation assay","journal":"Journal of microbiology (Seoul, Korea)","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid interaction with functional follow-up, single study","pmids":["18159223"],"is_preprint":false},{"year":2020,"finding":"IFITM2 restricts pseudorabies virus (PRV) by interfering with viral cell binding and entry, and IFITM2-mediated inhibition of PRV entry requires the cholesterol pathway in endosomes.","method":"Overexpression/knockdown antiviral assays, cholesterol pathway inhibitor experiments, viral attachment and entry assays","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 3 — functional entry assays with pharmacological mechanistic follow-up, single lab","pmids":["32745511"],"is_preprint":false},{"year":2019,"finding":"G3BP1 and G3BP2 RNA-binding proteins are required for accumulation of IFITM2 protein, regulating IFITM2 translation through interaction with IFITM2 3'-UTRs and via the MEK signaling pathway.","method":"G3BP knockdown, MEK pathway inhibition, 3'-UTR reporter assays, Western blotting in MCF7 cells","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — translational regulation shown by knockdown and 3'-UTR assays, single lab","pmids":["31172368"],"is_preprint":false},{"year":2023,"finding":"IFITM2 binds to MDA5 (detected by co-immunoprecipitation) and promotes IFN-β production; knockdown of MDA5 significantly inhibits IFITM2-mediated activation of the IFN-β signaling pathway; the N-terminal domain of IFITM2 is required for both antiviral activity and IFN-β activation.","method":"Co-immunoprecipitation, siRNA knockdown of MDA5, IFN-β luciferase reporter assay, N-terminal domain deletion/mutation analysis","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with functional epistasis, single lab","pmids":["37112847"],"is_preprint":false},{"year":2024,"finding":"IFITM1 and IFITM2 inhibit senecavirus A replication by activating the RIG-I signaling pathway, forming a positive feedback loop; conserved domains of IFITM2 are required for this activity; overexpression/knockdown experiments demonstrate regulation of IFN-β, ISG15, IRF3, IRF7, and inflammatory cytokines.","method":"Overexpression and siRNA knockdown, viral replication assays, cytokine/ISG expression profiling","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 3 — gain- and loss-of-function with pathway readout, single study","pmids":["38484578"],"is_preprint":false},{"year":2025,"finding":"IFITM2 acts as a DNA receptor on CD4+ T cells that senses neutrophil extracellular trap (NET)-DNA during sepsis; IFITM2 is recruited to the cell membrane via NET-anchored ENO1 (through myeloperoxidase), and activated IFITM2 signals through RAP1B and downstream ERK to promote Treg differentiation and immunosuppression.","method":"Co-immunoprecipitation, siRNA knockdown, ENO1 inhibition in vivo, Treg differentiation assays, sepsis mouse model (CLP)","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, KD, in vivo), single lab, novel mechanism","pmids":["40892462"],"is_preprint":false},{"year":2023,"finding":"An anti-IFITM2 monoclonal antibody targeting the N-terminus of IFITM2 impairs Spike-mediated SARS-CoV-2 internalization, reduces cytopathic effects and syncytia formation; also reduces HSV- and RSV-dependent cytopathic effects, indicating IFITM2's direct role in mediating viral entry.","method":"Monoclonal antibody blocking experiment, SARS-CoV-2 infection and syncytia formation assays, cytopathic effect measurement","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 3 — antibody blocking with functional readout, single lab","pmids":["36669656"],"is_preprint":false},{"year":2025,"finding":"IFITM2 is essential for endocytic processes in radial glial cells (RGCs) during neocortex development; the YXXø endocytic motif governs IFITM2 subcellular localization and endocytic vesicle formation; K82 and K87 residues interact with phosphoinositides to promote vesicle formation; IFITM2 loss reduces AKT and GSK3β phosphorylation; PI(3,4)P2 polarization on the ventricular side is linked to IFITM2-dependent vesicle formation.","method":"IFITM2 conditional knockout, endocytic motif mutagenesis, phosphoinositide binding assays, live imaging of endosome formation, phospho-AKT/GSK3β Western blotting, human and mouse models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, mutagenesis, biochemical binding, signaling readouts) in mouse and human models","pmids":["40052215"],"is_preprint":false},{"year":2024,"finding":"IFITM2 knockdown in osteogenic C3H10T1/2 cells inhibits osteogenic differentiation, calcium deposition, and osteogenic marker expression; IFITM2 overexpression enhances canonical Wnt signaling (luciferase assay); IFITM2 colocalizes with SP7 in metaphyseal bone and growth plate.","method":"siRNA knockdown, osteogenic differentiation assays, Wnt luciferase reporter assay, immunohistochemistry co-localization","journal":"Intractable & rare diseases research","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with pathway reporter, single lab","pmids":["38404731"],"is_preprint":false},{"year":2026,"finding":"IFITM2 (and IFITM3) physically interact with MYCT1, a pan-endothelial protein; loss of MYCT1 causes IFITM2/3 accumulation in early endosomes, promoting excessive endolysosomal degradation and mTORC1 hyperactivation, limiting white adipose tissue energy storage capacity.","method":"Endothelial-specific MYCT1 knockout mouse, co-immunoprecipitation of MYCT1-IFITM2/3 complex, endosome imaging, mTORC1 activity assays, WAT expansion measurements","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP interaction with in vivo KO and mechanistic pathway readouts, single lab","pmids":["41880193"],"is_preprint":false}],"current_model":"IFITM2 is an interferon-induced transmembrane protein that localizes predominantly to late endosomes and lysosomes (via a YXXø endocytic motif and phosphoinositide interactions), where it blocks viral membrane fusion to restrict a broad range of enveloped viruses (HCV, SARS-CoV-2, RVFV, HIV-1, PRV); it also functions as a proviral co-factor hijacked by SARS-CoV-2 for efficient lung cell entry, acts as a pro-apoptotic factor (caspase-dependent, p53-independent), interacts with MDA5 to amplify type I IFN signaling, functions as a NET-DNA receptor on CD4+ T cells coupling ENO1/MPO recruitment to RAP1B-ERK-mediated Treg differentiation, regulates endocytosis in neural radial glial cells through Wnt/AKT signaling, and forms a complex with MYCT1 to regulate endolysosomal trafficking and mTORC1 activity in endothelial cells."},"narrative":{"teleology":[{"year":2003,"claim":"The first interaction partner of IFITM2 was identified—adenovirus precursor terminal protein—suggesting IFITM2 could link viral infection to host apoptosis, though the physiological relevance of this interaction remained uncertain.","evidence":"Yeast two-hybrid screen from HeLa cDNA library with inducible expression and DNA fragmentation assays","pmids":["18159223"],"confidence":"Medium","gaps":["Yeast two-hybrid interaction not confirmed by reciprocal Co-IP or endogenous validation","Relevance to natural adenovirus infection cycle unclear","Mechanism linking pTP binding to apoptosis induction unresolved"]},{"year":2009,"claim":"IFITM2 was established as a pro-apoptotic effector that induces G1 arrest and caspase-dependent cell death independently of p53, revealing a non-antiviral function for the protein.","evidence":"Transient transfection in multiple cell lines with Annexin-V, TUNEL, cell cycle analysis, and caspase inhibitor experiments; siRNA knockdown partially rescued etoposide/UV-induced apoptosis","pmids":["19544527"],"confidence":"High","gaps":["Downstream apoptotic pathway (intrinsic vs. extrinsic) not fully delineated","Physiological contexts triggering IFITM2-mediated apoptosis in vivo unknown","Relationship between membrane topology and apoptotic function unresolved"]},{"year":2013,"claim":"The antiviral mechanism of IFITM2 was pinpointed to inhibition of viral membrane fusion at endosomes rather than effects on attachment or endocytosis, establishing IFITM2 as a fusion-stage restriction factor distinct from IFITM1 in its vesicular localization.","evidence":"Overexpression/knockdown with step-by-step entry dissection (attachment, endocytosis, fusion) for RVFV; subcellular localization imaging","pmids":["23720721"],"confidence":"High","gaps":["Biophysical mechanism by which IFITM2 prevents lipid mixing/hemifusion not determined","Whether IFITM2 alters membrane rigidity or curvature directly untested"]},{"year":2015,"claim":"The molecular determinants of IFITM2 anti-HCV activity and localization were defined: S-palmitoylation is essential for antiviral function, while the N-terminal tyrosine-based motif governs late endosome/lysosome targeting but is dispensable for restriction.","evidence":"Site-directed mutagenesis of palmitoylation sites and tyrosine residue, subcellular fractionation and colocalization, HCV entry assays in hepatocytes","pmids":["26354436"],"confidence":"High","gaps":["How palmitoylation mechanistically enables fusion block unclear","Identity of palmitoyl acyltransferase(s) modifying IFITM2 not established"]},{"year":2017,"claim":"A truncated IFITM2 isoform (Δ20) was shown to differentially restrict X4-tropic but not R5-tropic HIV-1, with coreceptor C-terminal identity determining susceptibility, revealing tropism-dependent antiviral specificity.","evidence":"Overexpression/siRNA in macrophages and dendritic cells, chimeric CXCR4/CCR5 swap constructs, HIV-1 entry assays","pmids":["28630320"],"confidence":"High","gaps":["How the CCR5 C-terminus confers resistance to Δ20 IFITM2 restriction mechanistically unknown","In vivo relevance of Δ20 isoform expression levels in CD4+ T cells not quantified"]},{"year":2019,"claim":"Post-transcriptional regulation of IFITM2 was uncovered: G3BP1/2 RNA-binding proteins control IFITM2 protein accumulation via 3'-UTR interactions and MEK signaling, establishing a stress granule–linked regulatory axis.","evidence":"G3BP knockdown, MEK inhibition, 3'-UTR reporter assays in MCF7 cells","pmids":["31172368"],"confidence":"Medium","gaps":["Direct RNA-binding sites on IFITM2 mRNA not mapped","Whether G3BP-IFITM2 regulation operates during viral infection untested","Single cell line used"]},{"year":2020,"claim":"IFITM2 was shown to restrict pseudorabies virus via a cholesterol-dependent mechanism in endosomes, extending its antiviral breadth to alphaherpesviruses and implicating cholesterol homeostasis in its restriction mechanism.","evidence":"Overexpression/knockdown antiviral assays with cholesterol pathway inhibitors and viral attachment/entry assays","pmids":["32745511"],"confidence":"Medium","gaps":["Whether IFITM2 directly alters cholesterol distribution or acts indirectly unresolved","Single lab, not independently replicated"]},{"year":2021,"claim":"IFITM2 was identified as the predominant IFITM restricting SARS-CoV-2, but the polybasic furin cleavage site in Spike enables partial evasion by permitting pH-independent entry, revealing a viral countermeasure to IFITM-mediated restriction.","evidence":"siRNA knockdown, pseudovirus and authentic SARS-CoV-2 assays, pharmacological entry-route dissection, IFN treatment with IFITM2 depletion","pmids":["33563656"],"confidence":"High","gaps":["Whether SARS-CoV-2 variants with altered furin site processing differentially evade IFITM2 not systematically tested at time of study"]},{"year":2022,"claim":"A paradigm shift emerged: endogenous IFITM2 in lung cells acts as a proviral cofactor hijacked by SARS-CoV-2, with depletion reducing viral production by >4 logs across all variants of concern; an N-terminal antibody blocked this proviral role, establishing IFITM2 as a therapeutic target.","evidence":"siRNA knockdown in Calu-3 and iPSC-derived alveolar type II cells, authentic SARS-CoV-2 VOC infection, anti-IFITM2 antibody treatment","pmids":["35543509"],"confidence":"High","gaps":["Molecular mechanism by which IFITM2 facilitates rather than restricts SARS-CoV-2 entry not fully delineated","Whether proviral function extends to other coronaviruses unknown"]},{"year":2023,"claim":"IFITM2 was found to interact with MDA5 and amplify IFN-β production, connecting the protein to innate immune signaling beyond its direct antiviral membrane function; the N-terminal domain is required for both antiviral activity and IFN-β activation.","evidence":"Co-immunoprecipitation, MDA5 knockdown epistasis, IFN-β luciferase reporter, N-terminal deletion analysis","pmids":["37112847"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation or endogenous stoichiometry assessment","Whether IFITM2-MDA5 interaction occurs in primary immune cells untested","Domain on MDA5 mediating interaction not mapped"]},{"year":2024,"claim":"IFITM2 was shown to promote osteogenic differentiation via enhancement of canonical Wnt signaling, broadening its functional repertoire to skeletal biology.","evidence":"siRNA knockdown in C3H10T1/2 cells, osteogenic assays, Wnt luciferase reporter, immunohistochemistry in bone","pmids":["38404731"],"confidence":"Medium","gaps":["In vivo bone phenotype from IFITM2 loss not shown","Mechanism of Wnt pathway activation by IFITM2 not determined","Single cell line used"]},{"year":2025,"claim":"IFITM2 was established as a critical endocytic regulator in radial glial cells during cortical development: the YXXφ motif and K82/K87 phosphoinositide-binding residues drive vesicle formation and polarized PI(3,4)P2 distribution, coupling endocytosis to AKT/GSK3β/Wnt signaling.","evidence":"Conditional IFITM2 knockout, endocytic motif mutagenesis, phosphoinositide binding assays, live imaging, phospho-signaling Western blots in mouse and human models","pmids":["40052215"],"confidence":"High","gaps":["Whether IFITM2 endocytic function in RGCs also modulates viral susceptibility in the developing brain untested","Structural basis of phosphoinositide interaction not resolved"]},{"year":2025,"claim":"IFITM2 was discovered to function as a NET-DNA receptor on CD4+ T cells, coupling ENO1/MPO-mediated membrane recruitment to RAP1B-ERK signaling and Treg differentiation during sepsis, establishing a novel immunoregulatory role entirely distinct from antiviral defense.","evidence":"Co-immunoprecipitation, siRNA knockdown, ENO1 inhibition in vivo, Treg differentiation assays, CLP sepsis mouse model","pmids":["40892462"],"confidence":"Medium","gaps":["Whether IFITM2-mediated Treg induction operates in non-sepsis inflammatory contexts unknown","Direct DNA-binding domain on IFITM2 not mapped","Single lab, novel mechanism awaiting independent confirmation"]},{"year":2026,"claim":"IFITM2 was found to form a physical complex with MYCT1 in endothelial cells, where loss of MYCT1 causes IFITM2 accumulation in early endosomes leading to mTORC1 hyperactivation and impaired adipose tissue energy storage, linking IFITM2 to endolysosomal trafficking and metabolic regulation.","evidence":"Endothelial-specific MYCT1 knockout mouse, Co-IP of MYCT1–IFITM2 complex, endosome imaging, mTORC1 activity assays","pmids":["41880193"],"confidence":"Medium","gaps":["Whether IFITM2 directly regulates mTORC1 or acts through altered cargo delivery not resolved","Stoichiometry and structural basis of MYCT1-IFITM2 complex unknown","Single lab study"]},{"year":null,"claim":"The biophysical mechanism by which IFITM2 blocks viral membrane fusion—whether through direct alteration of membrane curvature, rigidity, cholesterol distribution, or hemifusion intermediate stabilization—remains structurally unresolved; additionally, how the same protein can act as both an antiviral restriction factor and a proviral cofactor for SARS-CoV-2 depending on cellular context is mechanistically unexplained.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of IFITM2 in a membrane environment","Molecular switch between antiviral and proviral functions not identified","Integration of antiviral, apoptotic, signaling, and developmental functions into a unified model lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3,4,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,13,15]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,3,4,7,9,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,10,11,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,15]}],"complexes":["MYCT1-IFITM2/3 endolysosomal complex"],"partners":["MDA5","MYCT1","RAP1B","ENO1","G3BP1","G3BP2","SP7"],"other_free_text":[]},"mechanistic_narrative":"IFITM2 is an interferon-induced transmembrane protein that functions primarily as a broad-spectrum antiviral effector and endosomal trafficking regulator, with additional roles in apoptosis, innate immune signaling, and cell differentiation. Localized predominantly to late endosomes and lysosomes via a YXXφ endocytic motif and phosphoinositide interactions, IFITM2 restricts enveloped viruses—including HCV, SARS-CoV-2, RVFV, HIV-1, and PRV—by blocking viral membrane fusion at the endosomal entry stage, a function dependent on S-palmitoylation [PMID:26354436, PMID:23720721, PMID:33563656, PMID:28630320]; paradoxically, endogenous IFITM2 in lung epithelial cells is hijacked by SARS-CoV-2 as a proviral cofactor essential for efficient replication of all variants of concern [PMID:35543509]. Beyond antiviral defense, IFITM2 promotes caspase-dependent, p53-independent apoptosis [PMID:19544527], interacts with MDA5 to amplify IFN-β signaling [PMID:37112847], senses neutrophil extracellular trap DNA on CD4+ T cells via ENO1/MPO to drive RAP1B-ERK–mediated Treg differentiation [PMID:40892462], regulates endocytic vesicle formation and AKT/Wnt signaling in neural radial glial cells during cortical development [PMID:40052215], and forms a complex with MYCT1 to govern endolysosomal trafficking and mTORC1 activity in endothelial cells [PMID:41880193]."},"prefetch_data":{"uniprot":{"accession":"Q01629","full_name":"Interferon-induced transmembrane protein 2","aliases":["Dispanin subfamily A member 2c","DSPA2c","Interferon-inducible protein 1-8D"],"length_aa":132,"mass_kda":14.6,"function":"IFN-induced antiviral protein which inhibits the entry of viruses to the host cell cytoplasm, permitting endocytosis, but preventing subsequent viral fusion and release of viral contents into the cytosol (PubMed:26354436, PubMed:33563656). Active against multiple viruses, including influenza A virus, SARS coronaviruses (SARS-CoV and SARS-CoV-2), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and vesicular stomatitis virus (VSV) (PubMed:26354436, PubMed:33239446, PubMed:33270927, PubMed:33563656). Can inhibit: influenza virus hemagglutinin protein-mediated viral entry, MARV and EBOV GP1,2-mediated viral entry, SARS-CoV and SARS-CoV-2 S protein-mediated viral entry and VSV G protein-mediated viral entry (PubMed:33563656). Induces cell cycle arrest and mediates apoptosis by caspase activation and in p53-independent manner. In hepatocytes, IFITM proteins act in a coordinated manner to restrict HCV infection by targeting the endocytosed HCV virion for lysosomal degradation (PubMed:26354436). IFITM2 and IFITM3 display anti-HCV activity that may complement the anti-HCV activity of IFITM1 by inhibiting the late stages of HCV entry, possibly in a coordinated manner by trapping the virion in the endosomal pathway and targeting it for degradation at the lysosome (PubMed:26354436)","subcellular_location":"Cell membrane; Lysosome membrane; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q01629/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IFITM2","classification":"Common Essential","n_dependent_lines":615,"n_total_lines":1208,"dependency_fraction":0.5091059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFITM2","total_profiled":1310},"omim":[{"mim_id":"614757","title":"INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 5; IFITM5","url":"https://www.omim.org/entry/614757"},{"mim_id":"606480","title":"ZINC METALLOPROTEINASE STE24; ZMPSTE24","url":"https://www.omim.org/entry/606480"},{"mim_id":"605579","title":"INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 3; IFITM3","url":"https://www.omim.org/entry/605579"},{"mim_id":"605578","title":"INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 2; IFITM2","url":"https://www.omim.org/entry/605578"},{"mim_id":"604456","title":"INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 1; IFITM1","url":"https://www.omim.org/entry/604456"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFITM2"},"hgnc":{"alias_symbol":["1-8D","DSPA2c"],"prev_symbol":[]},"alphafold":{"accession":"Q01629","domains":[{"cath_id":"1.10.287","chopping":"54-132","consensus_level":"medium","plddt":73.5356,"start":54,"end":132}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01629","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01629-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01629-F1-predicted_aligned_error_v6.png","plddt_mean":61.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFITM2","jax_strain_url":"https://www.jax.org/strain/search?query=IFITM2"},"sequence":{"accession":"Q01629","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01629.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01629/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01629"}},"corpus_meta":[{"pmid":"26354436","id":"PMC_26354436","title":"The Interferon-induced Transmembrane Proteins, IFITM1, IFITM2, and IFITM3 Inhibit Hepatitis C Virus Entry.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26354436","citation_count":148,"is_preprint":false},{"pmid":"33563656","id":"PMC_33563656","title":"The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/33563656","citation_count":114,"is_preprint":false},{"pmid":"23720721","id":"PMC_23720721","title":"IFITM-2 and IFITM-3 but not IFITM-1 restrict Rift Valley fever virus.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23720721","citation_count":109,"is_preprint":false},{"pmid":"28223169","id":"PMC_28223169","title":"IGF1/IGF1R/STAT3 signaling-inducible IFITM2 promotes gastric cancer growth and metastasis.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/28223169","citation_count":74,"is_preprint":false},{"pmid":"19449377","id":"PMC_19449377","title":"Molecular characterization of the response to chemotherapy in conventional osteosarcomas: predictive value of HSD17B10 and IFITM2.","date":"2009","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19449377","citation_count":38,"is_preprint":false},{"pmid":"19544527","id":"PMC_19544527","title":"The human 1-8D gene (IFITM2) is a novel p53 independent pro-apoptotic gene.","date":"2009","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19544527","citation_count":36,"is_preprint":false},{"pmid":"35543509","id":"PMC_35543509","title":"SARS-CoV-2 Variants of Concern Hijack IFITM2 for Efficient Replication in Human Lung Cells.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/35543509","citation_count":32,"is_preprint":false},{"pmid":"28630320","id":"PMC_28630320","title":"Δ20 IFITM2 differentially restricts X4 and R5 HIV-1.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28630320","citation_count":31,"is_preprint":false},{"pmid":"32745511","id":"PMC_32745511","title":"Host antiviral protein IFITM2 restricts pseudorabies virus replication.","date":"2020","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/32745511","citation_count":23,"is_preprint":false},{"pmid":"31172368","id":"PMC_31172368","title":"G3BP1 and G3BP2 regulate translation of interferon-stimulated genes: IFITM1, IFITM2 and IFITM3 in the cancer cell line MCF7.","date":"2019","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31172368","citation_count":20,"is_preprint":false},{"pmid":"33308825","id":"PMC_33308825","title":"Predicative value of IFITM2 in renal clear cell carcinoma: IFITM2 is associated with lymphatic metastasis and poor clinical outcome.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33308825","citation_count":17,"is_preprint":false},{"pmid":"37112847","id":"PMC_37112847","title":"IFITM2 Presents Antiviral Response through Enhancing Type I IFN Signaling Pathway.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/37112847","citation_count":11,"is_preprint":false},{"pmid":"31148967","id":"PMC_31148967","title":"NP and NS1 proteins of H5N1 virus significantly upregulated IFITM1, IFITM2, and IFITM3 in A549 cells.","date":"2019","source":"African health 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hepatocytes, and restricts HCV at the late entry stage; S-palmitoylation of IFITM2 is essential for anti-HCV activity, while a conserved N-terminal tyrosine residue governs protein localization but is dispensable for antiviral activity.\",\n      \"method\": \"Subcellular fractionation/colocalization imaging, site-directed mutagenesis of palmitoylation sites and tyrosine residue, antiviral entry assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, mutagenesis, functional assay) in a single well-cited study\",\n      \"pmids\": [\"26354436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFITM2 (and IFITM3, but not IFITM1) restricts Rift Valley fever virus primarily by preventing viral membrane fusion with endosomes, with no effect on virion attachment, endocytosis, or viral replication kinetics; IFITM2 occupies vesicular compartments distinct from those of IFITM1 and expands vesicular/acidified compartments when overexpressed.\",\n      \"method\": \"Overexpression and knockdown antiviral assays, entry step dissection (attachment, endocytosis, fusion assays), subcellular localization imaging\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods dissecting entry step with localization in a well-cited study\",\n      \"pmids\": [\"23720721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFITM2 is the predominant IFITM family member restricting SARS-CoV-2 replication; restriction is governed by route of viral entry, with the polybasic furin cleavage site in spike allowing pH-independent entry that partially evades IFITM2-mediated restriction; targeted depletion of IFITM2 alleviates type I IFN-mediated inhibition of SARS-CoV-2 replication.\",\n      \"method\": \"siRNA knockdown, pseudovirus and authentic SARS-CoV-2 infection assays, entry route pharmacological dissection, IFN treatment with IFITM2 depletion\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, entry pharmacology, pseudovirus/authentic virus) replicated across conditions\",\n      \"pmids\": [\"33563656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFITM2 acts as a proviral cofactor (hijacked by SARS-CoV-2) for efficient replication; depletion of endogenous IFITM2 in human lung cells reduces infectious virus production by all SARS-CoV-2 variants of concern by more than 4 orders of magnitude; an anti-IFITM2 N-terminal antibody inhibits VOC replication in iPSC-derived alveolar epithelial type II cells.\",\n      \"method\": \"siRNA knockdown, authentic SARS-CoV-2 VOC infection assays in Calu-3 cells and iPSC-derived cells, neutralizing antibody treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across five VOCs, multiple cell types, antibody validation\",\n      \"pmids\": [\"35543509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A 20-amino-acid N-terminal truncation isoform of IFITM2 (Δ20 IFITM2) differentially restricts X4-tropic but not R5-tropic HIV-1 by inhibiting viral entry; coreceptor identity (CXCR4 vs CCR5 C-terminus) determines susceptibility to Δ20 IFITM2-mediated restriction; Δ20 IFITM2 is expressed in CD4+ T cells and monocytes.\",\n      \"method\": \"Overexpression and siRNA depletion in monocyte-derived macrophages and dendritic cells, chimeric coreceptor swap constructs, entry assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform characterization with mechanistic chimera experiments and multiple cell types\",\n      \"pmids\": [\"28630320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IFITM2 (1-8D) functions as a pro-apoptotic gene independent of p53; transient expression causes G1 arrest followed by apoptosis (confirmed by Annexin-V and TUNEL); apoptosis induction requires caspase activity; knockdown of IFITM2 provides partial protection from etoposide- and UV-induced apoptosis; p53 expression downregulates IFITM2 protein levels.\",\n      \"method\": \"Transient transfection in multiple mammalian cell lines, cell cycle analysis, Annexin-V binding, TUNEL assay, caspase inhibitor experiments, siRNA knockdown\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal apoptosis assays with gain- and loss-of-function in multiple cell lines\",\n      \"pmids\": [\"19544527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IFITM2 (Inid/1-8D gene product) physically interacts with adenovirus precursor terminal protein (pTP), identified by yeast two-hybrid screen of HeLa cDNA library; expression of IFITM2 in adenovirus-infected cells induces apoptosis, suggesting the pTP-binding targets infected cells for apoptotic destruction as a host defense.\",\n      \"method\": \"Yeast two-hybrid screen, tetracycline-inducible expression, TdT assay, DNA fragmentation assay\",\n      \"journal\": \"Journal of microbiology (Seoul, Korea)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid interaction with functional follow-up, single study\",\n      \"pmids\": [\"18159223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFITM2 restricts pseudorabies virus (PRV) by interfering with viral cell binding and entry, and IFITM2-mediated inhibition of PRV entry requires the cholesterol pathway in endosomes.\",\n      \"method\": \"Overexpression/knockdown antiviral assays, cholesterol pathway inhibitor experiments, viral attachment and entry assays\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional entry assays with pharmacological mechanistic follow-up, single lab\",\n      \"pmids\": [\"32745511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"G3BP1 and G3BP2 RNA-binding proteins are required for accumulation of IFITM2 protein, regulating IFITM2 translation through interaction with IFITM2 3'-UTRs and via the MEK signaling pathway.\",\n      \"method\": \"G3BP knockdown, MEK pathway inhibition, 3'-UTR reporter assays, Western blotting in MCF7 cells\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — translational regulation shown by knockdown and 3'-UTR assays, single lab\",\n      \"pmids\": [\"31172368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM2 binds to MDA5 (detected by co-immunoprecipitation) and promotes IFN-β production; knockdown of MDA5 significantly inhibits IFITM2-mediated activation of the IFN-β signaling pathway; the N-terminal domain of IFITM2 is required for both antiviral activity and IFN-β activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of MDA5, IFN-β luciferase reporter assay, N-terminal domain deletion/mutation analysis\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional epistasis, single lab\",\n      \"pmids\": [\"37112847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFITM1 and IFITM2 inhibit senecavirus A replication by activating the RIG-I signaling pathway, forming a positive feedback loop; conserved domains of IFITM2 are required for this activity; overexpression/knockdown experiments demonstrate regulation of IFN-β, ISG15, IRF3, IRF7, and inflammatory cytokines.\",\n      \"method\": \"Overexpression and siRNA knockdown, viral replication assays, cytokine/ISG expression profiling\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — gain- and loss-of-function with pathway readout, single study\",\n      \"pmids\": [\"38484578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFITM2 acts as a DNA receptor on CD4+ T cells that senses neutrophil extracellular trap (NET)-DNA during sepsis; IFITM2 is recruited to the cell membrane via NET-anchored ENO1 (through myeloperoxidase), and activated IFITM2 signals through RAP1B and downstream ERK to promote Treg differentiation and immunosuppression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ENO1 inhibition in vivo, Treg differentiation assays, sepsis mouse model (CLP)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, KD, in vivo), single lab, novel mechanism\",\n      \"pmids\": [\"40892462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An anti-IFITM2 monoclonal antibody targeting the N-terminus of IFITM2 impairs Spike-mediated SARS-CoV-2 internalization, reduces cytopathic effects and syncytia formation; also reduces HSV- and RSV-dependent cytopathic effects, indicating IFITM2's direct role in mediating viral entry.\",\n      \"method\": \"Monoclonal antibody blocking experiment, SARS-CoV-2 infection and syncytia formation assays, cytopathic effect measurement\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — antibody blocking with functional readout, single lab\",\n      \"pmids\": [\"36669656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFITM2 is essential for endocytic processes in radial glial cells (RGCs) during neocortex development; the YXXø endocytic motif governs IFITM2 subcellular localization and endocytic vesicle formation; K82 and K87 residues interact with phosphoinositides to promote vesicle formation; IFITM2 loss reduces AKT and GSK3β phosphorylation; PI(3,4)P2 polarization on the ventricular side is linked to IFITM2-dependent vesicle formation.\",\n      \"method\": \"IFITM2 conditional knockout, endocytic motif mutagenesis, phosphoinositide binding assays, live imaging of endosome formation, phospho-AKT/GSK3β Western blotting, human and mouse models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, mutagenesis, biochemical binding, signaling readouts) in mouse and human models\",\n      \"pmids\": [\"40052215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFITM2 knockdown in osteogenic C3H10T1/2 cells inhibits osteogenic differentiation, calcium deposition, and osteogenic marker expression; IFITM2 overexpression enhances canonical Wnt signaling (luciferase assay); IFITM2 colocalizes with SP7 in metaphyseal bone and growth plate.\",\n      \"method\": \"siRNA knockdown, osteogenic differentiation assays, Wnt luciferase reporter assay, immunohistochemistry co-localization\",\n      \"journal\": \"Intractable & rare diseases research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with pathway reporter, single lab\",\n      \"pmids\": [\"38404731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IFITM2 (and IFITM3) physically interact with MYCT1, a pan-endothelial protein; loss of MYCT1 causes IFITM2/3 accumulation in early endosomes, promoting excessive endolysosomal degradation and mTORC1 hyperactivation, limiting white adipose tissue energy storage capacity.\",\n      \"method\": \"Endothelial-specific MYCT1 knockout mouse, co-immunoprecipitation of MYCT1-IFITM2/3 complex, endosome imaging, mTORC1 activity assays, WAT expansion measurements\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction with in vivo KO and mechanistic pathway readouts, single lab\",\n      \"pmids\": [\"41880193\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFITM2 is an interferon-induced transmembrane protein that localizes predominantly to late endosomes and lysosomes (via a YXXø endocytic motif and phosphoinositide interactions), where it blocks viral membrane fusion to restrict a broad range of enveloped viruses (HCV, SARS-CoV-2, RVFV, HIV-1, PRV); it also functions as a proviral co-factor hijacked by SARS-CoV-2 for efficient lung cell entry, acts as a pro-apoptotic factor (caspase-dependent, p53-independent), interacts with MDA5 to amplify type I IFN signaling, functions as a NET-DNA receptor on CD4+ T cells coupling ENO1/MPO recruitment to RAP1B-ERK-mediated Treg differentiation, regulates endocytosis in neural radial glial cells through Wnt/AKT signaling, and forms a complex with MYCT1 to regulate endolysosomal trafficking and mTORC1 activity in endothelial cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IFITM2 is an interferon-induced transmembrane protein that functions primarily as a broad-spectrum antiviral effector and endosomal trafficking regulator, with additional roles in apoptosis, innate immune signaling, and cell differentiation. Localized predominantly to late endosomes and lysosomes via a YXXφ endocytic motif and phosphoinositide interactions, IFITM2 restricts enveloped viruses—including HCV, SARS-CoV-2, RVFV, HIV-1, and PRV—by blocking viral membrane fusion at the endosomal entry stage, a function dependent on S-palmitoylation [PMID:26354436, PMID:23720721, PMID:33563656, PMID:28630320]; paradoxically, endogenous IFITM2 in lung epithelial cells is hijacked by SARS-CoV-2 as a proviral cofactor essential for efficient replication of all variants of concern [PMID:35543509]. Beyond antiviral defense, IFITM2 promotes caspase-dependent, p53-independent apoptosis [PMID:19544527], interacts with MDA5 to amplify IFN-β signaling [PMID:37112847], senses neutrophil extracellular trap DNA on CD4+ T cells via ENO1/MPO to drive RAP1B-ERK–mediated Treg differentiation [PMID:40892462], regulates endocytic vesicle formation and AKT/Wnt signaling in neural radial glial cells during cortical development [PMID:40052215], and forms a complex with MYCT1 to govern endolysosomal trafficking and mTORC1 activity in endothelial cells [PMID:41880193].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"The first interaction partner of IFITM2 was identified—adenovirus precursor terminal protein—suggesting IFITM2 could link viral infection to host apoptosis, though the physiological relevance of this interaction remained uncertain.\",\n      \"evidence\": \"Yeast two-hybrid screen from HeLa cDNA library with inducible expression and DNA fragmentation assays\",\n      \"pmids\": [\"18159223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Yeast two-hybrid interaction not confirmed by reciprocal Co-IP or endogenous validation\", \"Relevance to natural adenovirus infection cycle unclear\", \"Mechanism linking pTP binding to apoptosis induction unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"IFITM2 was established as a pro-apoptotic effector that induces G1 arrest and caspase-dependent cell death independently of p53, revealing a non-antiviral function for the protein.\",\n      \"evidence\": \"Transient transfection in multiple cell lines with Annexin-V, TUNEL, cell cycle analysis, and caspase inhibitor experiments; siRNA knockdown partially rescued etoposide/UV-induced apoptosis\",\n      \"pmids\": [\"19544527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream apoptotic pathway (intrinsic vs. extrinsic) not fully delineated\", \"Physiological contexts triggering IFITM2-mediated apoptosis in vivo unknown\", \"Relationship between membrane topology and apoptotic function unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The antiviral mechanism of IFITM2 was pinpointed to inhibition of viral membrane fusion at endosomes rather than effects on attachment or endocytosis, establishing IFITM2 as a fusion-stage restriction factor distinct from IFITM1 in its vesicular localization.\",\n      \"evidence\": \"Overexpression/knockdown with step-by-step entry dissection (attachment, endocytosis, fusion) for RVFV; subcellular localization imaging\",\n      \"pmids\": [\"23720721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biophysical mechanism by which IFITM2 prevents lipid mixing/hemifusion not determined\", \"Whether IFITM2 alters membrane rigidity or curvature directly untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The molecular determinants of IFITM2 anti-HCV activity and localization were defined: S-palmitoylation is essential for antiviral function, while the N-terminal tyrosine-based motif governs late endosome/lysosome targeting but is dispensable for restriction.\",\n      \"evidence\": \"Site-directed mutagenesis of palmitoylation sites and tyrosine residue, subcellular fractionation and colocalization, HCV entry assays in hepatocytes\",\n      \"pmids\": [\"26354436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How palmitoylation mechanistically enables fusion block unclear\", \"Identity of palmitoyl acyltransferase(s) modifying IFITM2 not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A truncated IFITM2 isoform (Δ20) was shown to differentially restrict X4-tropic but not R5-tropic HIV-1, with coreceptor C-terminal identity determining susceptibility, revealing tropism-dependent antiviral specificity.\",\n      \"evidence\": \"Overexpression/siRNA in macrophages and dendritic cells, chimeric CXCR4/CCR5 swap constructs, HIV-1 entry assays\",\n      \"pmids\": [\"28630320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the CCR5 C-terminus confers resistance to Δ20 IFITM2 restriction mechanistically unknown\", \"In vivo relevance of Δ20 isoform expression levels in CD4+ T cells not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Post-transcriptional regulation of IFITM2 was uncovered: G3BP1/2 RNA-binding proteins control IFITM2 protein accumulation via 3'-UTR interactions and MEK signaling, establishing a stress granule–linked regulatory axis.\",\n      \"evidence\": \"G3BP knockdown, MEK inhibition, 3'-UTR reporter assays in MCF7 cells\",\n      \"pmids\": [\"31172368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding sites on IFITM2 mRNA not mapped\", \"Whether G3BP-IFITM2 regulation operates during viral infection untested\", \"Single cell line used\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"IFITM2 was shown to restrict pseudorabies virus via a cholesterol-dependent mechanism in endosomes, extending its antiviral breadth to alphaherpesviruses and implicating cholesterol homeostasis in its restriction mechanism.\",\n      \"evidence\": \"Overexpression/knockdown antiviral assays with cholesterol pathway inhibitors and viral attachment/entry assays\",\n      \"pmids\": [\"32745511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFITM2 directly alters cholesterol distribution or acts indirectly unresolved\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"IFITM2 was identified as the predominant IFITM restricting SARS-CoV-2, but the polybasic furin cleavage site in Spike enables partial evasion by permitting pH-independent entry, revealing a viral countermeasure to IFITM-mediated restriction.\",\n      \"evidence\": \"siRNA knockdown, pseudovirus and authentic SARS-CoV-2 assays, pharmacological entry-route dissection, IFN treatment with IFITM2 depletion\",\n      \"pmids\": [\"33563656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SARS-CoV-2 variants with altered furin site processing differentially evade IFITM2 not systematically tested at time of study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A paradigm shift emerged: endogenous IFITM2 in lung cells acts as a proviral cofactor hijacked by SARS-CoV-2, with depletion reducing viral production by >4 logs across all variants of concern; an N-terminal antibody blocked this proviral role, establishing IFITM2 as a therapeutic target.\",\n      \"evidence\": \"siRNA knockdown in Calu-3 and iPSC-derived alveolar type II cells, authentic SARS-CoV-2 VOC infection, anti-IFITM2 antibody treatment\",\n      \"pmids\": [\"35543509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which IFITM2 facilitates rather than restricts SARS-CoV-2 entry not fully delineated\", \"Whether proviral function extends to other coronaviruses unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IFITM2 was found to interact with MDA5 and amplify IFN-β production, connecting the protein to innate immune signaling beyond its direct antiviral membrane function; the N-terminal domain is required for both antiviral activity and IFN-β activation.\",\n      \"evidence\": \"Co-immunoprecipitation, MDA5 knockdown epistasis, IFN-β luciferase reporter, N-terminal deletion analysis\",\n      \"pmids\": [\"37112847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or endogenous stoichiometry assessment\", \"Whether IFITM2-MDA5 interaction occurs in primary immune cells untested\", \"Domain on MDA5 mediating interaction not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IFITM2 was shown to promote osteogenic differentiation via enhancement of canonical Wnt signaling, broadening its functional repertoire to skeletal biology.\",\n      \"evidence\": \"siRNA knockdown in C3H10T1/2 cells, osteogenic assays, Wnt luciferase reporter, immunohistochemistry in bone\",\n      \"pmids\": [\"38404731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo bone phenotype from IFITM2 loss not shown\", \"Mechanism of Wnt pathway activation by IFITM2 not determined\", \"Single cell line used\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"IFITM2 was established as a critical endocytic regulator in radial glial cells during cortical development: the YXXφ motif and K82/K87 phosphoinositide-binding residues drive vesicle formation and polarized PI(3,4)P2 distribution, coupling endocytosis to AKT/GSK3β/Wnt signaling.\",\n      \"evidence\": \"Conditional IFITM2 knockout, endocytic motif mutagenesis, phosphoinositide binding assays, live imaging, phospho-signaling Western blots in mouse and human models\",\n      \"pmids\": [\"40052215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFITM2 endocytic function in RGCs also modulates viral susceptibility in the developing brain untested\", \"Structural basis of phosphoinositide interaction not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"IFITM2 was discovered to function as a NET-DNA receptor on CD4+ T cells, coupling ENO1/MPO-mediated membrane recruitment to RAP1B-ERK signaling and Treg differentiation during sepsis, establishing a novel immunoregulatory role entirely distinct from antiviral defense.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, ENO1 inhibition in vivo, Treg differentiation assays, CLP sepsis mouse model\",\n      \"pmids\": [\"40892462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFITM2-mediated Treg induction operates in non-sepsis inflammatory contexts unknown\", \"Direct DNA-binding domain on IFITM2 not mapped\", \"Single lab, novel mechanism awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"IFITM2 was found to form a physical complex with MYCT1 in endothelial cells, where loss of MYCT1 causes IFITM2 accumulation in early endosomes leading to mTORC1 hyperactivation and impaired adipose tissue energy storage, linking IFITM2 to endolysosomal trafficking and metabolic regulation.\",\n      \"evidence\": \"Endothelial-specific MYCT1 knockout mouse, Co-IP of MYCT1–IFITM2 complex, endosome imaging, mTORC1 activity assays\",\n      \"pmids\": [\"41880193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFITM2 directly regulates mTORC1 or acts through altered cargo delivery not resolved\", \"Stoichiometry and structural basis of MYCT1-IFITM2 complex unknown\", \"Single lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biophysical mechanism by which IFITM2 blocks viral membrane fusion—whether through direct alteration of membrane curvature, rigidity, cholesterol distribution, or hemifusion intermediate stabilization—remains structurally unresolved; additionally, how the same protein can act as both an antiviral restriction factor and a proviral cofactor for SARS-CoV-2 depending on cellular context is mechanistically unexplained.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of IFITM2 in a membrane environment\", \"Molecular switch between antiviral and proviral functions not identified\", \"Integration of antiviral, apoptotic, signaling, and developmental functions into a unified model lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3, 4, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 13, 15]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 10, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 15]}\n    ],\n    \"complexes\": [\n      \"MYCT1-IFITM2/3 endolysosomal complex\"\n    ],\n    \"partners\": [\n      \"MDA5\",\n      \"MYCT1\",\n      \"RAP1B\",\n      \"ENO1\",\n      \"G3BP1\",\n      \"G3BP2\",\n      \"SP7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}