{"gene":"IFITM1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2005,"finding":"Mouse Ifitm1 acts via a repulsive mechanism to direct primordial germ cell (PGC) transit from mesoderm into endoderm; this repulsive activity is mediated by the N-terminal extracellular domain of IFITM1 and cannot be substituted by the N-terminal domain of another family member.","method":"Mouse genetic loss-of-function and domain-swap experiments; in vivo cell migration assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo loss-of-function with specific PGC migration phenotype, replicated with domain-swap rescue experiments","pmids":["16326387"],"is_preprint":false},{"year":1993,"finding":"IFITM1 (RBP9-27) binds RNA in vitro and inhibits HIV-1 Rev-dependent posttranscriptional steps of viral gene expression after transfection into human cells, identifying an interferon-induced antiviral mechanism targeting Rev function.","method":"cDNA library screen for RRE-binding proteins, in vitro RNA-binding assay, transfection + HIV-1 expression assay","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro binding assay plus cell-based functional assay; single lab study","pmids":["7680491"],"is_preprint":false},{"year":1996,"finding":"Human IFITM1 (9-27 protein) has intrinsic antiviral activity against vesicular stomatitis virus (VSV) when constitutively expressed; its intracellular distribution resembles cytoskeleton-associated proteins. No significant inhibition of influenza virus was observed.","method":"Constitutive cDNA expression in mouse cells; single-cell immunofluorescence; virus infection assays","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 — direct loss/gain-of-function with viral plaque assay; single lab","pmids":["8727077"],"is_preprint":false},{"year":2006,"finding":"IFITM1 is required for the antiproliferative action of IFN-γ downstream of STAT1; it inhibits ERK activity, enhances p53 transcriptional activity, and stabilizes p53 by inhibiting phosphorylation of p53 on Thr55. Suppression of IFITM1 blocks IFN-γ antiproliferation and confers tumorigenicity.","method":"Overexpression and siRNA knockdown in hepatocytes; ERK activity assay; p53 transcriptional reporter; p53 phosphorylation assay; nude mouse tumor assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal mechanistic assays in single study with clear pathway placement","pmids":["16847454"],"is_preprint":false},{"year":2009,"finding":"IFITM1 localizes to caveolae of the plasma membrane and physically interacts with caveolin-1 (CAV-1) via its hydrophobic transmembrane domains; this interaction enhances CAV-1's inhibitory effect on ERK phosphorylation and downstream transcription.","method":"Immunofluorescence co-localization; Co-IP; deletion mutagenesis; ERK phosphorylation assay; CAV-1 siRNA knockdown","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping and functional ERK assay; single lab","pmids":["19499152"],"is_preprint":false},{"year":2010,"finding":"CD147 activation by Cyclophilin A induces IFITM1 expression via ERK, PI3K, and NF-κB signaling pathways; cross-linking of IFITM1 with a monoclonal antibody induces pro-inflammatory mediators IL-8 and MMP-9, indicating IFITM1 mediates inflammatory activation of macrophages.","method":"Pharmacological inhibition of signaling pathways; RT-PCR; Western blot; IFITM1 cross-linking with mAb","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 3 — functional pathway inhibitor studies with two orthogonal readouts; single lab","pmids":["20847954"],"is_preprint":false},{"year":2012,"finding":"IFITM1 is a hepatocyte tight junction protein that interacts with HCV co-receptors CD81 and occludin to disrupt viral entry; IFITM1 accumulates at hepatic tight junctions during IFN therapy in HCV-infected patient liver.","method":"Co-IP of IFITM1 with CD81 and occludin; immunofluorescence localization; gain/loss-of-function in hepatocytes; patient liver IHC during IFN therapy","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with known HCV co-receptors, direct localization at tight junctions, functional viral entry assay, patient tissue validation","pmids":["22996292"],"is_preprint":false},{"year":2013,"finding":"IFITM1 adopts more than one membrane topology co-existing in cellular membranes; its antiviral breadth is regulated by a unique C-terminal non-canonical dibasic sorting signal (KRXX) that governs intracellular distribution by binding to adaptor protein complex 3 (AP-3). Mutating this motif (KR/AA) increases restriction of certain retroviruses and redistributes IFITM1 to CD63-positive multivesicular bodies away from LAMP1-positive lysosomes.","method":"Deconvolution microscopy; substituted cysteine accessibility method (SCAM) for topology; Co-IP with AP-3; AP-3 knockdown; mutagenesis; pseudovirus infection assays","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including SCAM topology mapping, Co-IP, mutagenesis, and localization with functional consequence","pmids":["25527505"],"is_preprint":false},{"year":2013,"finding":"Murine IFITM1 is palmitoylated on one nonconserved cysteine and three conserved cysteines; palmitoylation is required for anti-influenza A virus activity and regulates protein stability by preventing proteasomal degradation. Modification of the nonconserved C-terminal cysteine supports an intramembrane topology.","method":"Palmitoylation assay; cysteine mutagenesis; proteasome inhibitor assay; influenza A virus infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — direct palmitoylation assay with mutagenesis and functional antiviral readout; topology implication","pmids":["23804635"],"is_preprint":false},{"year":2015,"finding":"S-palmitoylation of IFITM1 (and IFITM2/3) is essential for anti-HCV activity in hepatocytes. IFITM1 localizes at the plasma membrane/tight junctions and co-localizes with CD81, and its anti-HCV activity operates at the entry level. Mutation of the conserved N-terminal tyrosine of IFITM2/3 results in an IFITM1-like phenotype with plasma membrane localization and retained anti-HCV activity.","method":"Palmitoylation inhibition; site-directed mutagenesis; subcellular fractionation; confocal localization; HCV entry/replication assays","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — palmitoylation assay with mutagenesis and antiviral functional readout; multiple orthogonal methods","pmids":["26354436"],"is_preprint":false},{"year":2014,"finding":"The C-terminal 9 amino acids of human IFITM1 suppress antiviral restriction of some viruses by controlling subcellular localization; a deletion mutant (Δ117-125) shifts IFITM1 predominantly to the plasma membrane and inhibits HIV-1 entry. Mouse IFITM1, which naturally lacks 19 C-terminal amino acids relative to human IFITM1, similarly restricts HIV-1 entry.","method":"C-terminal deletion mutagenesis; subcellular localization by microscopy; HIV-1 entry assay; comparison of human vs. mouse IFITM1","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with localization and functional entry assay; single lab","pmids":["25738301"],"is_preprint":false},{"year":2014,"finding":"HIV-1 can evolve to evade IFITM1 restriction through mutations in Vpu (introducing a premature stop at position 35) and Env (G367E at the CD4-binding site); these mutations enhance cell-to-cell virus transmission rather than overcoming p24 downregulation caused by IFITM1.","method":"Serial passage of HIV-1 in IFITM1-expressing cells; whole-genome sequencing; functional cell-to-cell transmission assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 — directed evolution experiment with mechanism dissection; single lab","pmids":["24725927"],"is_preprint":false},{"year":2015,"finding":"IFITM1 promotes colorectal cancer cell migration/invasion via Caveolin-1 (CAV1) as a downstream target; CAV1 knockdown abrogates the siIFITM1-mediated inhibition of cell invasion, and IFITM1 expression inversely correlates with CAV1 in patient tumors.","method":"siRNA knockdown of IFITM1 and CAV1; cell migration/invasion assays; correlation analysis in patient tumor cohort","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis knockdown experiment with functional invasion assay; single lab","pmids":["26259513"],"is_preprint":false},{"year":2016,"finding":"IFITM1 overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a STAT2-dependent manner; STAT2 activates IFITM1 promoter activity via the chromatin remodeler BRG1, and loss of STAT2 abolishes IFITM1 expression and reduces proliferation, migration, and invasion.","method":"siRNA/shRNA knockdown; luciferase promoter assay; STAT2/BRG1 interaction studies; migration/invasion assays","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with mechanistic promoter dissection; single lab","pmids":["26897526"],"is_preprint":false},{"year":2017,"finding":"Loss of IFITM1 in AI-resistant MCF-7:5C breast cancer cells induces p21 transcription, expression, and nuclear localization via JAK/STAT pathway activation, suppressing tumor growth and invasion in vivo.","method":"Lentiviral shRNA knockdown; orthotopic and mammary intraductal mouse models; p21 quantification; JAK/STAT inhibitor studies","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model with mechanistic pathway dissection; single lab","pmids":["28411130"],"is_preprint":false},{"year":2017,"finding":"IFITM1 coordinates with IFITM3 to regulate IFNγ-stimulated protein synthesis; SWATH-IP mass spectrometry of SBP-tagged IFITM1 identified ISG15 and HLA-B as dominant co-associated proteins. Proximity ligation assays confirmed IFITM1/3 interaction with HLA-B. Loss of IFITM1/3 attenuates ISG15ylation and reduces cell surface HLA-B expression.","method":"SWATH-IP mass spectrometry; pulse SILAC; proximity ligation assay; CRISPR-Cas9 double knockout; flow cytometry for surface HLA-B","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal proteomic and cell biological methods with isogenic CRISPR KO model","pmids":["30951861"],"is_preprint":false},{"year":2017,"finding":"STAT1 binds to an IFN-responsive enhancer located 35 kb upstream of the IFITM3 gene promoter upon IFN treatment; this enhancer physically clusters with IFITM1, 2, and 3 gene loci via long-range chromatin interactions and is required for coordinated IFN-induced expression of all three IFITM genes and antiviral resistance to influenza A virus.","method":"ChIP; EMSA; luciferase reporter; CRISPR-Cas9 enhancer truncation; chromosome conformation capture (3C)","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods with in vivo CRISPR validation and functional antiviral readout","pmids":["28511927"],"is_preprint":false},{"year":2017,"finding":"IFITM1 suppresses human endogenous retroviruses (HERVs) in human embryonic stem cells by regulating epigenetic modifications; IFITM1 KO leads to higher HERV expression and reduced trimethylation of H3K9 at HERV loci.","method":"CRISPR/Cas9 IFITM1 knockout in hESCs; qRT-PCR; ChIP for H3K9me3","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 — clean CRISPR KO with epigenetic mechanism; single lab","pmids":["28781951"],"is_preprint":false},{"year":2019,"finding":"MUC1 interacts with STAT1 via JAK/STAT signaling to stimulate IFITM1 transcription in AI-resistant breast cancer cells; siRNA knockdown or pharmacological inhibition of MUC1 abrogates IFITM1 expression and induces cell death. In vivo, estrogen and ruxolitinib reduce MUC1, P-STAT1, and IFITM1 expression.","method":"siRNA knockdown; pharmacological inhibition; Co-IP of MUC1-STAT1; in vivo tumor model; Western blot","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic Co-IP with functional KD and in vivo validation; single lab","pmids":["30655323"],"is_preprint":false},{"year":2019,"finding":"G3BP1 and G3BP2 are essential for accumulation of IFITM1, IFITM2, and IFITM3 proteins; they regulate IFITM1-3 translation through the MEK pathway and through interaction with the 3'-UTRs of IFITM transcripts.","method":"G3BP knockdown; MEK pathway inhibition; 3'-UTR interaction assays; Western blot","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — mechanistic inference from knockdown without direct protein-RNA interaction validation","pmids":["31172368"],"is_preprint":false},{"year":2019,"finding":"IFITM1 overexpression promotes VSMC proliferation, migration, and macrophage-like transdifferentiation via the c-Src/MAPK/GATA2/E2F2 signaling pathway; IFITM1 overexpression in ApoE-/- mice accelerates atherosclerotic plaque formation.","method":"Overexpression/knockdown; Western blot for p-Src, p-MAPK, p-GATA2, E2F2; cell viability, wound healing, transwell assays; ApoE-/- mouse model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway mapped by multiple phospho-protein assays with in vivo validation; single lab","pmids":["40466954"],"is_preprint":false},{"year":2021,"finding":"IFITM1 knockdown in triple-negative breast cancer cells activates NF-κB as a downstream target, as revealed by RNA-seq. IFITM1 loss reduces proliferation, colony formation, migration, and invasion in vitro and in vivo; the NF-κB inhibitor parthenolide suppresses both IFITM1 expression and TNBC tumor growth.","method":"siRNA/CRISPR-Cas9 KO; RNA-seq; NF-κB functional assays; orthotopic mouse model; drug treatment","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with RNA-seq pathway mapping and in vivo validation; single lab","pmids":["34022283"],"is_preprint":false},{"year":2021,"finding":"IFITM1 expression (induced by APC mutation/Wnt activation) reduces extracellular vesicle (EV) uptake by colorectal cancer cells; IFITM1 inactivation enhances EV uptake and eliminates proliferation differences between IFITM1-high and IFITM1-low CRC subpopulations.","method":"Mouse and patient-derived organoids; IFITM1 knockdown; EV uptake quantification; proliferation assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD with mechanistic EV uptake readout in organoid model; single lab","pmids":["34609520"],"is_preprint":false},{"year":2022,"finding":"IFITM1 SRSF1 (splicing factor) and HLA-B as interaction partners in cervical cancer cells; IFITM1/3 associate with SRSF1 in the cytosol and with HLA-B mRNA in response to IFNγ, facilitating ribosomal translation of HLA-B without altering mRNA levels. IFITM1/3 double-null cells show reduced 80S ribosomal fraction, partially reversed by IFITM1/3 complementation.","method":"SBP-tagged IFITM1 pulldown/MS; in situ proximity ligation assay; RNA-protein PLA; ribosome profiling by sucrose gradient sedimentation; RNA-seq; RT-qPCR","journal":"Biomolecules","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (MS, PLA, ribosome profiling) with isogenic rescue; single lab with strong methodological rigor","pmids":["36008984"],"is_preprint":false},{"year":2022,"finding":"CircVPS13C decreases IFITM1 mRNA stability by competitively interacting with RRBP1 (a ribosome-binding protein of the ER membrane), thereby suppressing IFITM1 expression and activating MAPK and apoptosis-associated downstream signaling in pituitary adenoma cells.","method":"CircRNA pulldown; RNA-seq; gain/loss-of-function; rescue experiments; in vivo mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA pulldown with rescue experiments and in vivo validation; novel mRNA stability mechanism; single lab","pmids":["35091683"],"is_preprint":false},{"year":2023,"finding":"IFITM1 mediates immune surveillance of brain-metastatic lung cancer cells: high IFITM1 expression causes cancer cells to secrete complement component 3 (C3), which activates microglia, and increases MHC class I surface expression to enhance CD8+ T cell cytolytic activity. IFITM1 loss promotes brain colonization in vivo genome-wide CRISPR screen.","method":"In vivo genome-wide CRISPR-Cas9 screen; C3 secretion assay; flow cytometry for MHC-I; microglia phagocytosis and CD8+ T cell killing assays; mouse brain metastasis model","journal":"EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genome-wide in vivo CRISPR screen plus multiple mechanistic orthogonal assays; rigorous","pmids":["36799040"],"is_preprint":false},{"year":2023,"finding":"IFITM1 inhibits trophoblast invasion; IFN-β treatment upregulates IFITMs and reduces invasive ability of extravillous cytotrophoblasts, and transduction experiments confirmed IFITM1 specifically contributes to decreased cell invasion. High IFITM1 is found in CMV- and bacterial-infected human placentas.","method":"In vitro/ex vivo trophoblast invasion models; lentiviral IFITM1 transduction; poly(I:C) in vivo mouse model; human pathological placental sections","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — direct transduction experiment with invasion assay plus in vivo model and patient tissue; single lab","pmids":["37434700"],"is_preprint":false},{"year":2023,"finding":"IFITM1 enhances non-enveloped Aichi virus (AiV) RNA replication by facilitating cholesterol transport to the Golgi; IFITM1 localizes to viral RNA replication sites, interacts with viral proteins and host Golgi proteins ACBD3, PI4KB, and OSBP, and overexpressed IFITM1 facilitates late endosome-to-Golgi cholesterol transport.","method":"Co-IP of IFITM1 with viral and host proteins; immunofluorescence localization; IFITM1 knockdown; pharmacological inhibition of cholesterol transport; cholesterol imaging","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 — multiple Co-IP partners identified, direct localization at replication sites, KD functional assay, pharmacological rescue; single lab with multiple orthogonal methods","pmids":["37252940"],"is_preprint":false},{"year":2023,"finding":"IFITM1 and IFITM3 reduce HIV-1 infectivity when incorporated into progeny virions; IFITM3 additionally reduces HIV-1 Env processing and incorporation into virions, whereas IFITM1 does not affect Env clustering (shown by super-resolution imaging).","method":"Pseudovirus infectivity assays; super-resolution imaging of Env distribution; Western blot for Env processing","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 — super-resolution imaging plus functional infectivity assays; mechanistic distinction between IFITM1 and IFITM3 effects; single lab","pmids":["38140631"],"is_preprint":false},{"year":2023,"finding":"Oncostatin M induces IFITM1 expression via JAK-STAT signaling (STAT1-IRF9 transcription factor complex), and IFITM1 acts as an HBV restriction factor mediating OSM's anti-HBV activity in vitro and in vivo.","method":"RNA-seq; JAK-STAT pathway analysis; HBV replication assays in cells and rAAV8-HBV mice; ELISA","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq-guided mechanism with in vivo validation; single lab","pmids":["37879404"],"is_preprint":false},{"year":2019,"finding":"HBV core protein (HBc) inhibits IFNα-induced IFITM1 expression by interacting with BAF200, disrupting stability of the PBAF chromatin remodeling complex; basal IFITM1 expression depends on BAF200 rather than the JAK-STAT1 pathway.","method":"Yeast two-hybrid; Co-IP in 293T, HepG2 and HepG2-NTCP cells; siRNA knockdown; HBV replication assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP in multiple cell lines with functional antiviral readout; mechanistic dissection of basal vs. IFN-induced IFITM1 regulation; single lab","pmids":["31075894"],"is_preprint":false},{"year":2025,"finding":"ABHD17A physically interacts with IFITM1 and increases IFITM1 S-palmitoylation by downregulating the depalmitoylase ABHD16A, thereby enhancing IFITM1 antiviral activity; ABHD16A catalyzes depalmitoylation of IFITM1 and negatively regulates its antiviral function.","method":"Co-IP; acyl-PEGyl exchange gel-shift (APEGS) palmitoylation assay; siRNA/CRISPR KO; antiviral assays","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct palmitoylation assay with Co-IP and functional antiviral readout; single lab","pmids":["40723864"],"is_preprint":false},{"year":2024,"finding":"ABHD16A catalyzes depalmitoylation of IFITM1 and negatively regulates its anti-HBV activity; CRISPR KO of ABHD16A in HepG2.215 cells increases IFITM1 palmitoylation and enhances HBV restriction.","method":"Co-IP; APEGS palmitoylation assay; CRISPR/Cas9 KO of IFITM1 and ABHD16A; HBV replication assays","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct palmitoylation assay with CRISPR-based mechanistic validation; single lab","pmids":["40434075"],"is_preprint":false},{"year":2024,"finding":"Swine RNF5 ubiquitinates ABHD16A at residues K3 and K452, targeting it for proteasomal degradation; this prevents ABHD16A-mediated depalmitoylation of IFITM1, thereby restoring IFITM1 antiviral activity. This regulatory axis balances antiviral immune responses.","method":"AlphaFold2-based PPI prediction; immunofluorescence; Co-IP; ubiquitination assay; site-directed mutagenesis of K3/K452; IFITM1 palmitoylation assay; antiviral assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 1-2 — biochemical ubiquitination assay with mutagenesis and palmitoylation readout; single lab","pmids":["39601593"],"is_preprint":false},{"year":2024,"finding":"Biochemical characterization of recombinant IFITM1 reveals three conformational variants: monomer, dimer, and highly stable oligomer. The N-terminal region contains a structural motif important for oligomer formation, identified by HDX mass spectrometry and two-site ELISA. Dimer is less stable than oligomer to reducing agents and thermal denaturation.","method":"Size exclusion chromatography; circular dichroism thermal denaturation; reducing agent treatment; two-site ELISA; HDX mass spectrometry","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — direct biochemical characterization of recombinant protein with multiple biophysical methods; single lab","pmids":["38379409"],"is_preprint":false},{"year":2025,"finding":"IFITM1 is predominantly expressed in limbal epithelial stem/early transient amplifying (eTA) cells and positively regulates their proliferation and expansion after corneal wounding via inhibition of OVOL1 (a negative regulator of epithelial cell proliferation). AAV-mediated in vivo IFITM1 knockdown attenuates stem/eTA cell expansion after corneal injury.","method":"Single-cell RNA-seq; AAV-mediated in vivo knockdown; IFITM1 overexpression in human limbal epithelial cells; OVOL1 expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo AAV KD with scRNA-seq mechanism; epistasis with OVOL1; single lab","pmids":["40372397"],"is_preprint":false},{"year":2024,"finding":"Hydroquinone (benzene metabolite) impairs trophoblast migration and invasion via activation of the AhR pathway, which reduces Twist1 and subsequently IFITM1 expression; IFITM1 overexpression rescues impaired trophoblast migration, establishing the AhR-Twist1-IFITM1 axis as a regulator of trophoblast invasion.","method":"3D invasion/migration model; AhR pathway activation; Twist1 and IFITM1 qPCR and Western blot; IFITM1 overexpression rescue","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway dissection with rescue experiment; single lab","pmids":["39173312"],"is_preprint":false},{"year":2023,"finding":"Invasive FoxM1 phosphorylated at Ser25 by PLK1 upregulates IFITM1 expression through the STING-TBK1-IRF3 signaling axis in lung adenocarcinoma cells with phosphomimetic FoxM1.","method":"Immunoprecipitation; LC-MS/MS; kinase assay; site-directed mutagenesis; chromatin immunoprecipitation; microarray analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — kinase assay with mutagenesis and ChIP linking PLK1-FoxM1 to IFITM1 via STING pathway; single lab","pmids":["37968723"],"is_preprint":false},{"year":2018,"finding":"PITX2 transcriptionally activates IFITM1, and the resulting PITX2/IFITM1 cascade enhances IFNα-induced AKT activation, mediating letrozole resistance in breast cancer; siRNA ablation of IFITM1 abolishes IFNα-elicited AKT phosphorylation even in PITX2-overexpressing cells.","method":"Luciferase transcription assay; siRNA knockdown; AKT phosphorylation assay; xenograft model; Western blot","journal":"Cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 — transcription assay plus epistasis knockdown with AKT pathway readout; single lab","pmids":["30025446"],"is_preprint":false}],"current_model":"IFITM1 is an interferon-stimulated transmembrane protein that restricts diverse viral infections primarily by blocking membrane fusion at the plasma membrane or endosomal compartments; its antiviral breadth and potency are critically regulated by S-palmitoylation on conserved and nonconserved cysteines (written by DHHC enzymes, erased by ABHD16A which is itself regulated by ABHD17A and RNF5-mediated ubiquitination), and by a C-terminal dibasic sorting signal (KRXX) that controls AP-3-dependent subcellular distribution; at the plasma membrane, IFITM1 interacts with caveolin-1 via its transmembrane domains to enhance inhibition of ERK signaling and with tight junction proteins CD81 and occludin to block HCV entry; in the nucleus/cytosol it connects to STAT2/BRG1 and MUC1/STAT1 transcriptional complexes to regulate its own expression; it also associates with SRSF1 and HLA-B mRNA to facilitate ribosomal translation of MHC class I molecules, enabling immune surveillance; in development it acts as a repulsive cue directing primordial germ cell migration via its N-terminal extracellular domain, and in trophoblasts it supports invasion through an AhR-Twist1-IFITM1 axis and limbal stem cell expansion via OVOL1 inhibition."},"narrative":{"teleology":[{"year":1993,"claim":"The initial discovery that IFITM1 binds RNA and inhibits HIV-1 Rev-dependent post-transcriptional gene expression established it as an interferon-induced antiviral effector, but left its mechanism of action and breadth of viral targets unknown.","evidence":"cDNA library screen for RRE-binding proteins with in vitro RNA-binding and HIV-1 expression assays in human cells","pmids":["7680491"],"confidence":"Medium","gaps":["RNA-binding activity not confirmed by orthogonal methods","unclear whether antiviral effect requires direct RNA binding or operates via another mechanism","breadth of viral targets untested"]},{"year":1996,"claim":"Constitutive expression showed IFITM1 has intrinsic antiviral activity against VSV (but not influenza) and localizes like cytoskeleton-associated proteins, indicating virus-specific restriction independent of the broader IFN response.","evidence":"Constitutive cDNA expression in mouse cells with viral plaque assays and immunofluorescence","pmids":["8727077"],"confidence":"Medium","gaps":["mechanism of VSV restriction unresolved","apparent lack of influenza restriction later contradicted for mouse IFITM1 orthologue"]},{"year":2005,"claim":"Discovery that mouse Ifitm1 directs primordial germ cell migration via a repulsive mechanism mediated by its N-terminal extracellular domain revealed a developmental function entirely distinct from antiviral activity.","evidence":"Mouse genetic loss-of-function and domain-swap experiments with in vivo PGC migration assays","pmids":["16326387"],"confidence":"High","gaps":["molecular receptor for IFITM1 repulsive signal unknown","whether human IFITM1 retains PGC guidance function untested"]},{"year":2006,"claim":"Mechanistic dissection in hepatocytes showed IFITM1 mediates IFN-γ antiproliferative signaling by inhibiting ERK, enhancing p53 transcriptional activity, and stabilizing p53 through inhibition of Thr55 phosphorylation, establishing a tumor-suppressive signaling role.","evidence":"Overexpression/siRNA knockdown with ERK activity, p53 reporter, phospho-p53 assays, and nude mouse tumorigenicity","pmids":["16847454"],"confidence":"High","gaps":["direct biochemical target linking IFITM1 to ERK inhibition not identified","generalizability beyond hepatocytes unknown"]},{"year":2009,"claim":"The finding that IFITM1 localizes to caveolae and physically interacts with caveolin-1 via its transmembrane domains to enhance ERK inhibition provided a molecular platform for its antiproliferative signaling.","evidence":"Co-IP with deletion mutagenesis, immunofluorescence co-localization, and ERK phosphorylation assay","pmids":["19499152"],"confidence":"Medium","gaps":["stoichiometry and structural basis of IFITM1-CAV1 interaction unknown","single lab without reciprocal Co-IP validation"]},{"year":2012,"claim":"Identification of IFITM1 as a tight-junction protein interacting with HCV co-receptors CD81 and occludin established that its anti-HCV activity operates by disrupting viral entry at the plasma membrane, validated in patient liver during IFN therapy.","evidence":"Reciprocal Co-IP with CD81/occludin, immunofluorescence at tight junctions, HCV entry assay, and patient liver immunohistochemistry","pmids":["22996292"],"confidence":"High","gaps":["precise stoichiometry or structural basis of CD81/occludin disruption unknown","whether other tight-junction-tropic viruses are affected untested"]},{"year":2013,"claim":"Two studies resolved key post-translational regulatory mechanisms: palmitoylation of conserved cysteines is essential for antiviral activity and protein stability, while the C-terminal KRXX dibasic motif controls AP-3-dependent trafficking between plasma membrane and endosomal compartments, tuning antiviral breadth.","evidence":"Palmitoylation assay with cysteine mutagenesis and influenza assay; SCAM topology mapping, AP-3 Co-IP, and mutagenesis with pseudovirus assays","pmids":["23804635","25527505"],"confidence":"High","gaps":["identity of DHHC palmitoyltransferase(s) writing IFITM1 palmitoylation not determined","dual topology not yet integrated into structural model"]},{"year":2014,"claim":"The C-terminal 9 residues of human IFITM1 were shown to suppress antiviral restriction of HIV-1 by controlling localization; independently, HIV-1 evolved resistance via Vpu/Env mutations enhancing cell-to-cell transmission, defining an evolutionary arms race.","evidence":"C-terminal deletion mutagenesis with HIV-1 entry assay; serial passage/whole-genome sequencing with transmission assays","pmids":["25738301","24725927"],"confidence":"Medium","gaps":["structural basis for C-terminal autoinhibition unresolved","Vpu stop-codon mechanism not fully understood"]},{"year":2015,"claim":"Confirmation that palmitoylation is essential for anti-HCV activity and that IFITM1 localizes to tight junctions/plasma membrane to block HCV entry unified the palmitoylation and tight-junction interaction models.","evidence":"Palmitoylation inhibition and mutagenesis with HCV entry/replication assays and confocal localization","pmids":["26354436"],"confidence":"High","gaps":["which specific palmitoylation sites are most critical for HCV restriction not dissected"]},{"year":2017,"claim":"Multiple studies expanded IFITM1 beyond antiviral restriction: a distal IFN-responsive enhancer was shown to coordinate IFITM locus expression via STAT1-dependent chromatin looping; SWATH-IP proteomics identified ISG15 and HLA-B as major IFITM1-associated proteins; and IFITM1 KO in hESCs derepressed endogenous retroviruses with loss of H3K9me3, revealing epigenetic regulatory capacity.","evidence":"ChIP, 3C, CRISPR enhancer deletion with influenza assay; SWATH-IP MS with PLA and CRISPR double-KO; CRISPR IFITM1 KO in hESCs with qRT-PCR and H3K9me3 ChIP","pmids":["28511927","30951861","28781951"],"confidence":"High","gaps":["mechanism linking IFITM1 to H3K9 methyltransferase recruitment unknown","functional consequence of ISG15 association for antiviral activity untested"]},{"year":2019,"claim":"The transcriptional regulation of IFITM1 was further elaborated: MUC1-STAT1 interaction drives IFITM1 expression in breast cancer, BAF200/PBAF chromatin remodeling controls basal expression in hepatocytes, and HBV core protein antagonizes IFITM1 induction by destabilizing PBAF.","evidence":"Co-IP of MUC1-STAT1 with siRNA/drug in tumor models; yeast two-hybrid and Co-IP of HBc-BAF200 with siRNA and HBV replication assays","pmids":["30655323","31075894"],"confidence":"Medium","gaps":["direct STAT1 binding sites in IFITM1 promoter for MUC1-dependent activation not mapped","whether PBAF disruption by HBc is specific to IFITM1 or affects other ISGs"]},{"year":2022,"claim":"The mechanism by which IFITM1 promotes MHC class I surface expression was resolved: IFITM1 associates with splicing factor SRSF1 and HLA-B mRNA in the cytosol, facilitating ribosomal translation without altering mRNA levels, as demonstrated by ribosome profiling showing reduced 80S fraction in IFITM1/3-null cells.","evidence":"SBP-tagged pulldown/MS, RNA-protein PLA, ribosome profiling by sucrose gradient, isogenic CRISPR rescue","pmids":["36008984"],"confidence":"High","gaps":["specificity for HLA-B vs. other mRNAs not fully defined","structural basis of IFITM1-SRSF1-mRNA ternary complex unknown"]},{"year":2023,"claim":"Multiple discoveries broadened IFITM1 biology: it mediates immune surveillance of brain-metastatic cells via C3 secretion and MHC-I upregulation; it enhances non-enveloped Aichi virus replication by facilitating cholesterol transport to the Golgi; and it reduces extracellular vesicle uptake in colorectal cancer cells.","evidence":"In vivo CRISPR screen with C3/MHC-I/T cell assays; Co-IP of IFITM1 with ACBD3/PI4KB/OSBP, cholesterol imaging; organoid IFITM1 KD with EV uptake quantification","pmids":["36799040","37252940","34609520"],"confidence":"High","gaps":["mechanism by which IFITM1 promotes C3 secretion unknown","proviral cholesterol transport role potentially contradicts canonical antiviral paradigm—generalizability unclear","EV uptake mechanism not structurally resolved"]},{"year":2024,"claim":"The palmitoylation cycle was mechanistically resolved: ABHD16A was identified as the depalmitoylase of IFITM1, and RNF5 ubiquitinates ABHD16A at K3/K452 for proteasomal degradation, creating a ubiquitin-palmitoylation regulatory circuit that tunes antiviral potency. Biophysical characterization also revealed IFITM1 forms monomers, dimers, and highly stable oligomers with N-terminal region involvement.","evidence":"Co-IP, APEGS palmitoylation assay, CRISPR KO of ABHD16A with HBV assays; ubiquitination assay with K→R mutagenesis; SEC, CD, HDX-MS of recombinant IFITM1","pmids":["40434075","39601593","38379409"],"confidence":"Medium","gaps":["whether RNF5-ABHD16A axis operates in human cells (studied in swine)","functional significance of oligomeric states for antiviral activity or signaling unknown","identity of DHHC writer enzymes for IFITM1 still not established"]},{"year":2025,"claim":"ABHD17A was shown to physically interact with IFITM1 and enhance its palmitoylation by downregulating ABHD16A, adding another layer to the palmitoylation regulatory network; separately, IFITM1 was identified as a regulator of limbal epithelial stem cell expansion via OVOL1 inhibition after corneal injury.","evidence":"Co-IP and APEGS palmitoylation assay with antiviral assays; scRNA-seq with AAV-mediated in vivo KD and OVOL1 epistasis","pmids":["40723864","40372397"],"confidence":"Medium","gaps":["ABHD17A mechanism of ABHD16A downregulation not fully elucidated","OVOL1 inhibition mechanism (direct or indirect) not resolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis of IFITM1 membrane fusion inhibition, the identity of DHHC palmitoyltransferases that write IFITM1 palmitoylation, the molecular receptor mediating its developmental repulsive cue, reconciliation of proviral (Aichi virus) versus antiviral roles, and whether oligomeric states have distinct functional outputs.","evidence":"","pmids":[],"confidence":"High","gaps":["no high-resolution structure of IFITM1 in membrane context","DHHC writer enzymes unidentified","proviral vs. antiviral duality mechanism unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,12,22]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,23]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[27]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,6,7,9,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7,27]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[27]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,6,8,9,15,25,28,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,5,20,38]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,16,30]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,26,36]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,9,31,32,33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,14,21,25]}],"complexes":[],"partners":["CAV1","CD81","OCLN","SRSF1","ABHD16A","ABHD17A","ACBD3","AP3B1"],"other_free_text":[]},"mechanistic_narrative":"IFITM1 is an interferon-stimulated transmembrane protein with diverse roles in antiviral defense, immune surveillance, cell migration, and proliferation control. Its antiviral activity against HCV, HBV, HIV-1, VSV, and influenza depends on S-palmitoylation of conserved cysteines—written by DHHC enzymes and erased by ABHD16A (itself regulated by ABHD17A and RNF5-mediated ubiquitination)—and on a C-terminal dibasic KRXX sorting signal that governs AP-3-dependent subcellular distribution between plasma membrane and endosomal compartments [PMID:26354436, PMID:25527505, PMID:23804635, PMID:40434075, PMID:39601593]. At the plasma membrane, IFITM1 interacts with caveolin-1 to inhibit ERK signaling and p53 degradation, and with tight-junction proteins CD81 and occludin to block HCV entry; it also associates with SRSF1 and HLA-B mRNA to facilitate ribosomal translation of MHC class I, promoting immune surveillance including complement C3-mediated microglial activation and CD8+ T cell cytotoxicity against metastatic tumor cells [PMID:22996292, PMID:19499152, PMID:36008984, PMID:36799040]. In development, mouse IFITM1 acts as a repulsive cue directing primordial germ cell migration via its N-terminal extracellular domain, and in adult tissues it regulates trophoblast invasion and limbal stem cell expansion [PMID:16326387, PMID:37434700, PMID:40372397]."},"prefetch_data":{"uniprot":{"accession":"P13164","full_name":"Interferon-induced transmembrane protein 1","aliases":["Dispanin subfamily A member 2a","DSPA2a","Interferon-induced protein 17","Interferon-inducible protein 9-27","Leu-13 antigen"],"length_aa":125,"mass_kda":14.0,"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. 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) and hepatitis C virus (HCV) (PubMed:26354436, PubMed:33270927). Can inhibit: influenza virus hemagglutinin protein-mediated viral entry, MARV and EBOV GP1,2-mediated viral entry and SARS-CoV and SARS-CoV-2 S protein-mediated viral entry. Also implicated in cell adhesion and control of cell growth and migration (PubMed:33270927). Inhibits SARS-CoV-2 S protein-mediated syncytia formation (PubMed:33051876). Plays a key role in the antiproliferative action of IFN-gamma either by inhibiting the ERK activation or by arresting cell growth in G1 phase in a p53-dependent manner. Acts as a positive regulator of osteoblast differentiation. 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","url":"https://www.uniprot.org/uniprotkb/P13164/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFITM1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1090,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFITM1","total_profiled":1310},"omim":[{"mim_id":"617986","title":"LOW DENSITY LIPOPROTEIN RECEPTOR CLASS A DOMAIN-CONTAINING PROTEIN 3; LDLRAD3","url":"https://www.omim.org/entry/617986"},{"mim_id":"614757","title":"INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 5; IFITM5","url":"https://www.omim.org/entry/614757"},{"mim_id":"613493","title":"IMMUNODEFICIENCY, COMMON VARIABLE, 3; CVID3","url":"https://www.omim.org/entry/613493"},{"mim_id":"609539","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 2; ARID2","url":"https://www.omim.org/entry/609539"},{"mim_id":"606480","title":"ZINC METALLOPROTEINASE STE24; ZMPSTE24","url":"https://www.omim.org/entry/606480"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFITM1"},"hgnc":{"alias_symbol":["9-27","CD225","DSPA2a"],"prev_symbol":["IFI17"]},"alphafold":{"accession":"P13164","domains":[{"cath_id":"1.20.58","chopping":"37-125","consensus_level":"high","plddt":70.99,"start":37,"end":125}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13164","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13164-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13164-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFITM1","jax_strain_url":"https://www.jax.org/strain/search?query=IFITM1"},"sequence":{"accession":"P13164","fasta_url":"https://rest.uniprot.org/uniprotkb/P13164.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13164/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13164"}},"corpus_meta":[{"pmid":"16326387","id":"PMC_16326387","title":"IFITM/Mil/fragilis family proteins IFITM1 and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion.","date":"2005","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/16326387","citation_count":163,"is_preprint":false},{"pmid":"23658454","id":"PMC_23658454","title":"The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza A virus and dengue virus replication.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23658454","citation_count":156,"is_preprint":false},{"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":"22996292","id":"PMC_22996292","title":"IFITM1 is a tight junction protein that inhibits hepatitis C virus entry.","date":"2012","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22996292","citation_count":133,"is_preprint":false},{"pmid":"21976647","id":"PMC_21976647","title":"ISG56 and IFITM1 proteins inhibit hepatitis C virus replication.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21976647","citation_count":128,"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":"16847454","id":"PMC_16847454","title":"IFITM1 plays an essential role in the antiproliferative action of interferon-gamma.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16847454","citation_count":108,"is_preprint":false},{"pmid":"22787204","id":"PMC_22787204","title":"Hepatitis C virus infection modulates expression of interferon stimulatory gene IFITM1 by upregulating miR-130A.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22787204","citation_count":82,"is_preprint":false},{"pmid":"23804635","id":"PMC_23804635","title":"Palmitoylation on conserved and nonconserved cysteines of murine IFITM1 regulates its stability and anti-influenza A virus activity.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23804635","citation_count":72,"is_preprint":false},{"pmid":"26259513","id":"PMC_26259513","title":"IFITM1 promotes the metastasis of human colorectal cancer via CAV-1.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26259513","citation_count":69,"is_preprint":false},{"pmid":"20838853","id":"PMC_20838853","title":"Knockdown of interferon-induced transmembrane protein 1 (IFITM1) inhibits proliferation, migration, and invasion of glioma cells.","date":"2010","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20838853","citation_count":68,"is_preprint":false},{"pmid":"26897526","id":"PMC_26897526","title":"Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner.","date":"2016","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/26897526","citation_count":67,"is_preprint":false},{"pmid":"24827144","id":"PMC_24827144","title":"The antiviral restriction factors IFITM1, 2 and 3 do not inhibit infection of human papillomavirus, cytomegalovirus and adenovirus.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24827144","citation_count":66,"is_preprint":false},{"pmid":"15808405","id":"PMC_15808405","title":"The interferon-inducible 9-27 gene modulates the susceptibility to natural killer cells and the invasiveness of gastric 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restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain.","date":"2019","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/31826928","citation_count":35,"is_preprint":false},{"pmid":"15661263","id":"PMC_15661263","title":"Expression of IFITM1 in chronic myeloid leukemia patients.","date":"2005","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/15661263","citation_count":35,"is_preprint":false},{"pmid":"32394410","id":"PMC_32394410","title":"Deciphering the Roles of IFITM1 in Tumors.","date":"2020","source":"Molecular diagnosis & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32394410","citation_count":34,"is_preprint":false},{"pmid":"37968723","id":"PMC_37968723","title":"Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37968723","citation_count":34,"is_preprint":false},{"pmid":"31743714","id":"PMC_31743714","title":"Porcine IFITM1 is a host restriction factor that inhibits pseudorabies virus infection.","date":"2019","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31743714","citation_count":34,"is_preprint":false},{"pmid":"25738301","id":"PMC_25738301","title":"The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25738301","citation_count":33,"is_preprint":false},{"pmid":"25102331","id":"PMC_25102331","title":"Porcine reproductive and respiratory syndrome virus counteracts the porcine intrinsic virus restriction factors-IFITM1 and Tetherin in MARC-145 cells.","date":"2014","source":"Virus 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drug-response predictor in esophageal cancer: a novel screening method using microarray and identification of IFITM1 as a potent marker gene of CDDP response.","date":"2008","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18202764","citation_count":29,"is_preprint":false},{"pmid":"28700435","id":"PMC_28700435","title":"IFITM1 Outperforms CD10 in Differentiating Low-grade Endometrial Stromal Sarcomas From Smooth Muscle Neoplasms of the Uterus.","date":"2018","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/28700435","citation_count":28,"is_preprint":false},{"pmid":"34022283","id":"PMC_34022283","title":"Disrupting interferon-alpha and NF-kappaB crosstalk suppresses IFITM1 expression attenuating triple-negative breast cancer progression.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34022283","citation_count":27,"is_preprint":false},{"pmid":"29269892","id":"PMC_29269892","title":"miRNA-36 inhibits KSHV, EBV, HSV-2 infection of cells via stifling expression of interferon induced transmembrane protein 1 (IFITM1).","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29269892","citation_count":27,"is_preprint":false},{"pmid":"30655323","id":"PMC_30655323","title":"Interaction Between MUC1 and STAT1 Drives IFITM1 Overexpression in Aromatase Inhibitor-Resistant Breast Cancer Cells and Mediates Estrogen-Induced Apoptosis.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/30655323","citation_count":25,"is_preprint":false},{"pmid":"27920775","id":"PMC_27920775","title":"Human Papillomavirus Downregulates the Expression of IFITM1 and RIPK3 to Escape from IFNγ- and TNFα-Mediated Antiproliferative Effects and 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extracellular domain of IFITM1 and cannot be substituted by the N-terminal domain of another family member.\",\n      \"method\": \"Mouse genetic loss-of-function and domain-swap experiments; in vivo cell migration assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo loss-of-function with specific PGC migration phenotype, replicated with domain-swap rescue experiments\",\n      \"pmids\": [\"16326387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"IFITM1 (RBP9-27) binds RNA in vitro and inhibits HIV-1 Rev-dependent posttranscriptional steps of viral gene expression after transfection into human cells, identifying an interferon-induced antiviral mechanism targeting Rev function.\",\n      \"method\": \"cDNA library screen for RRE-binding proteins, in vitro RNA-binding assay, transfection + HIV-1 expression assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding assay plus cell-based functional assay; single lab study\",\n      \"pmids\": [\"7680491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Human IFITM1 (9-27 protein) has intrinsic antiviral activity against vesicular stomatitis virus (VSV) when constitutively expressed; its intracellular distribution resembles cytoskeleton-associated proteins. No significant inhibition of influenza virus was observed.\",\n      \"method\": \"Constitutive cDNA expression in mouse cells; single-cell immunofluorescence; virus infection assays\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct loss/gain-of-function with viral plaque assay; single lab\",\n      \"pmids\": [\"8727077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IFITM1 is required for the antiproliferative action of IFN-γ downstream of STAT1; it inhibits ERK activity, enhances p53 transcriptional activity, and stabilizes p53 by inhibiting phosphorylation of p53 on Thr55. Suppression of IFITM1 blocks IFN-γ antiproliferation and confers tumorigenicity.\",\n      \"method\": \"Overexpression and siRNA knockdown in hepatocytes; ERK activity assay; p53 transcriptional reporter; p53 phosphorylation assay; nude mouse tumor assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal mechanistic assays in single study with clear pathway placement\",\n      \"pmids\": [\"16847454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IFITM1 localizes to caveolae of the plasma membrane and physically interacts with caveolin-1 (CAV-1) via its hydrophobic transmembrane domains; this interaction enhances CAV-1's inhibitory effect on ERK phosphorylation and downstream transcription.\",\n      \"method\": \"Immunofluorescence co-localization; Co-IP; deletion mutagenesis; ERK phosphorylation assay; CAV-1 siRNA knockdown\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping and functional ERK assay; single lab\",\n      \"pmids\": [\"19499152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD147 activation by Cyclophilin A induces IFITM1 expression via ERK, PI3K, and NF-κB signaling pathways; cross-linking of IFITM1 with a monoclonal antibody induces pro-inflammatory mediators IL-8 and MMP-9, indicating IFITM1 mediates inflammatory activation of macrophages.\",\n      \"method\": \"Pharmacological inhibition of signaling pathways; RT-PCR; Western blot; IFITM1 cross-linking with mAb\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional pathway inhibitor studies with two orthogonal readouts; single lab\",\n      \"pmids\": [\"20847954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IFITM1 is a hepatocyte tight junction protein that interacts with HCV co-receptors CD81 and occludin to disrupt viral entry; IFITM1 accumulates at hepatic tight junctions during IFN therapy in HCV-infected patient liver.\",\n      \"method\": \"Co-IP of IFITM1 with CD81 and occludin; immunofluorescence localization; gain/loss-of-function in hepatocytes; patient liver IHC during IFN therapy\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with known HCV co-receptors, direct localization at tight junctions, functional viral entry assay, patient tissue validation\",\n      \"pmids\": [\"22996292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFITM1 adopts more than one membrane topology co-existing in cellular membranes; its antiviral breadth is regulated by a unique C-terminal non-canonical dibasic sorting signal (KRXX) that governs intracellular distribution by binding to adaptor protein complex 3 (AP-3). Mutating this motif (KR/AA) increases restriction of certain retroviruses and redistributes IFITM1 to CD63-positive multivesicular bodies away from LAMP1-positive lysosomes.\",\n      \"method\": \"Deconvolution microscopy; substituted cysteine accessibility method (SCAM) for topology; Co-IP with AP-3; AP-3 knockdown; mutagenesis; pseudovirus infection assays\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including SCAM topology mapping, Co-IP, mutagenesis, and localization with functional consequence\",\n      \"pmids\": [\"25527505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Murine IFITM1 is palmitoylated on one nonconserved cysteine and three conserved cysteines; palmitoylation is required for anti-influenza A virus activity and regulates protein stability by preventing proteasomal degradation. Modification of the nonconserved C-terminal cysteine supports an intramembrane topology.\",\n      \"method\": \"Palmitoylation assay; cysteine mutagenesis; proteasome inhibitor assay; influenza A virus infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct palmitoylation assay with mutagenesis and functional antiviral readout; topology implication\",\n      \"pmids\": [\"23804635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"S-palmitoylation of IFITM1 (and IFITM2/3) is essential for anti-HCV activity in hepatocytes. IFITM1 localizes at the plasma membrane/tight junctions and co-localizes with CD81, and its anti-HCV activity operates at the entry level. Mutation of the conserved N-terminal tyrosine of IFITM2/3 results in an IFITM1-like phenotype with plasma membrane localization and retained anti-HCV activity.\",\n      \"method\": \"Palmitoylation inhibition; site-directed mutagenesis; subcellular fractionation; confocal localization; HCV entry/replication assays\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — palmitoylation assay with mutagenesis and antiviral functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"26354436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The C-terminal 9 amino acids of human IFITM1 suppress antiviral restriction of some viruses by controlling subcellular localization; a deletion mutant (Δ117-125) shifts IFITM1 predominantly to the plasma membrane and inhibits HIV-1 entry. Mouse IFITM1, which naturally lacks 19 C-terminal amino acids relative to human IFITM1, similarly restricts HIV-1 entry.\",\n      \"method\": \"C-terminal deletion mutagenesis; subcellular localization by microscopy; HIV-1 entry assay; comparison of human vs. mouse IFITM1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with localization and functional entry assay; single lab\",\n      \"pmids\": [\"25738301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIV-1 can evolve to evade IFITM1 restriction through mutations in Vpu (introducing a premature stop at position 35) and Env (G367E at the CD4-binding site); these mutations enhance cell-to-cell virus transmission rather than overcoming p24 downregulation caused by IFITM1.\",\n      \"method\": \"Serial passage of HIV-1 in IFITM1-expressing cells; whole-genome sequencing; functional cell-to-cell transmission assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — directed evolution experiment with mechanism dissection; single lab\",\n      \"pmids\": [\"24725927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFITM1 promotes colorectal cancer cell migration/invasion via Caveolin-1 (CAV1) as a downstream target; CAV1 knockdown abrogates the siIFITM1-mediated inhibition of cell invasion, and IFITM1 expression inversely correlates with CAV1 in patient tumors.\",\n      \"method\": \"siRNA knockdown of IFITM1 and CAV1; cell migration/invasion assays; correlation analysis in patient tumor cohort\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis knockdown experiment with functional invasion assay; single lab\",\n      \"pmids\": [\"26259513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IFITM1 overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a STAT2-dependent manner; STAT2 activates IFITM1 promoter activity via the chromatin remodeler BRG1, and loss of STAT2 abolishes IFITM1 expression and reduces proliferation, migration, and invasion.\",\n      \"method\": \"siRNA/shRNA knockdown; luciferase promoter assay; STAT2/BRG1 interaction studies; migration/invasion assays\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with mechanistic promoter dissection; single lab\",\n      \"pmids\": [\"26897526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of IFITM1 in AI-resistant MCF-7:5C breast cancer cells induces p21 transcription, expression, and nuclear localization via JAK/STAT pathway activation, suppressing tumor growth and invasion in vivo.\",\n      \"method\": \"Lentiviral shRNA knockdown; orthotopic and mammary intraductal mouse models; p21 quantification; JAK/STAT inhibitor studies\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with mechanistic pathway dissection; single lab\",\n      \"pmids\": [\"28411130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IFITM1 coordinates with IFITM3 to regulate IFNγ-stimulated protein synthesis; SWATH-IP mass spectrometry of SBP-tagged IFITM1 identified ISG15 and HLA-B as dominant co-associated proteins. Proximity ligation assays confirmed IFITM1/3 interaction with HLA-B. Loss of IFITM1/3 attenuates ISG15ylation and reduces cell surface HLA-B expression.\",\n      \"method\": \"SWATH-IP mass spectrometry; pulse SILAC; proximity ligation assay; CRISPR-Cas9 double knockout; flow cytometry for surface HLA-B\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal proteomic and cell biological methods with isogenic CRISPR KO model\",\n      \"pmids\": [\"30951861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STAT1 binds to an IFN-responsive enhancer located 35 kb upstream of the IFITM3 gene promoter upon IFN treatment; this enhancer physically clusters with IFITM1, 2, and 3 gene loci via long-range chromatin interactions and is required for coordinated IFN-induced expression of all three IFITM genes and antiviral resistance to influenza A virus.\",\n      \"method\": \"ChIP; EMSA; luciferase reporter; CRISPR-Cas9 enhancer truncation; chromosome conformation capture (3C)\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods with in vivo CRISPR validation and functional antiviral readout\",\n      \"pmids\": [\"28511927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IFITM1 suppresses human endogenous retroviruses (HERVs) in human embryonic stem cells by regulating epigenetic modifications; IFITM1 KO leads to higher HERV expression and reduced trimethylation of H3K9 at HERV loci.\",\n      \"method\": \"CRISPR/Cas9 IFITM1 knockout in hESCs; qRT-PCR; ChIP for H3K9me3\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean CRISPR KO with epigenetic mechanism; single lab\",\n      \"pmids\": [\"28781951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MUC1 interacts with STAT1 via JAK/STAT signaling to stimulate IFITM1 transcription in AI-resistant breast cancer cells; siRNA knockdown or pharmacological inhibition of MUC1 abrogates IFITM1 expression and induces cell death. In vivo, estrogen and ruxolitinib reduce MUC1, P-STAT1, and IFITM1 expression.\",\n      \"method\": \"siRNA knockdown; pharmacological inhibition; Co-IP of MUC1-STAT1; in vivo tumor model; Western blot\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic Co-IP with functional KD and in vivo validation; single lab\",\n      \"pmids\": [\"30655323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"G3BP1 and G3BP2 are essential for accumulation of IFITM1, IFITM2, and IFITM3 proteins; they regulate IFITM1-3 translation through the MEK pathway and through interaction with the 3'-UTRs of IFITM transcripts.\",\n      \"method\": \"G3BP knockdown; MEK pathway inhibition; 3'-UTR interaction assays; Western blot\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic inference from knockdown without direct protein-RNA interaction validation\",\n      \"pmids\": [\"31172368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFITM1 overexpression promotes VSMC proliferation, migration, and macrophage-like transdifferentiation via the c-Src/MAPK/GATA2/E2F2 signaling pathway; IFITM1 overexpression in ApoE-/- mice accelerates atherosclerotic plaque formation.\",\n      \"method\": \"Overexpression/knockdown; Western blot for p-Src, p-MAPK, p-GATA2, E2F2; cell viability, wound healing, transwell assays; ApoE-/- mouse model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway mapped by multiple phospho-protein assays with in vivo validation; single lab\",\n      \"pmids\": [\"40466954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFITM1 knockdown in triple-negative breast cancer cells activates NF-κB as a downstream target, as revealed by RNA-seq. IFITM1 loss reduces proliferation, colony formation, migration, and invasion in vitro and in vivo; the NF-κB inhibitor parthenolide suppresses both IFITM1 expression and TNBC tumor growth.\",\n      \"method\": \"siRNA/CRISPR-Cas9 KO; RNA-seq; NF-κB functional assays; orthotopic mouse model; drug treatment\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with RNA-seq pathway mapping and in vivo validation; single lab\",\n      \"pmids\": [\"34022283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFITM1 expression (induced by APC mutation/Wnt activation) reduces extracellular vesicle (EV) uptake by colorectal cancer cells; IFITM1 inactivation enhances EV uptake and eliminates proliferation differences between IFITM1-high and IFITM1-low CRC subpopulations.\",\n      \"method\": \"Mouse and patient-derived organoids; IFITM1 knockdown; EV uptake quantification; proliferation assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with mechanistic EV uptake readout in organoid model; single lab\",\n      \"pmids\": [\"34609520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFITM1 SRSF1 (splicing factor) and HLA-B as interaction partners in cervical cancer cells; IFITM1/3 associate with SRSF1 in the cytosol and with HLA-B mRNA in response to IFNγ, facilitating ribosomal translation of HLA-B without altering mRNA levels. IFITM1/3 double-null cells show reduced 80S ribosomal fraction, partially reversed by IFITM1/3 complementation.\",\n      \"method\": \"SBP-tagged IFITM1 pulldown/MS; in situ proximity ligation assay; RNA-protein PLA; ribosome profiling by sucrose gradient sedimentation; RNA-seq; RT-qPCR\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (MS, PLA, ribosome profiling) with isogenic rescue; single lab with strong methodological rigor\",\n      \"pmids\": [\"36008984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircVPS13C decreases IFITM1 mRNA stability by competitively interacting with RRBP1 (a ribosome-binding protein of the ER membrane), thereby suppressing IFITM1 expression and activating MAPK and apoptosis-associated downstream signaling in pituitary adenoma cells.\",\n      \"method\": \"CircRNA pulldown; RNA-seq; gain/loss-of-function; rescue experiments; in vivo mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA pulldown with rescue experiments and in vivo validation; novel mRNA stability mechanism; single lab\",\n      \"pmids\": [\"35091683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM1 mediates immune surveillance of brain-metastatic lung cancer cells: high IFITM1 expression causes cancer cells to secrete complement component 3 (C3), which activates microglia, and increases MHC class I surface expression to enhance CD8+ T cell cytolytic activity. IFITM1 loss promotes brain colonization in vivo genome-wide CRISPR screen.\",\n      \"method\": \"In vivo genome-wide CRISPR-Cas9 screen; C3 secretion assay; flow cytometry for MHC-I; microglia phagocytosis and CD8+ T cell killing assays; mouse brain metastasis model\",\n      \"journal\": \"EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide in vivo CRISPR screen plus multiple mechanistic orthogonal assays; rigorous\",\n      \"pmids\": [\"36799040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM1 inhibits trophoblast invasion; IFN-β treatment upregulates IFITMs and reduces invasive ability of extravillous cytotrophoblasts, and transduction experiments confirmed IFITM1 specifically contributes to decreased cell invasion. High IFITM1 is found in CMV- and bacterial-infected human placentas.\",\n      \"method\": \"In vitro/ex vivo trophoblast invasion models; lentiviral IFITM1 transduction; poly(I:C) in vivo mouse model; human pathological placental sections\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transduction experiment with invasion assay plus in vivo model and patient tissue; single lab\",\n      \"pmids\": [\"37434700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM1 enhances non-enveloped Aichi virus (AiV) RNA replication by facilitating cholesterol transport to the Golgi; IFITM1 localizes to viral RNA replication sites, interacts with viral proteins and host Golgi proteins ACBD3, PI4KB, and OSBP, and overexpressed IFITM1 facilitates late endosome-to-Golgi cholesterol transport.\",\n      \"method\": \"Co-IP of IFITM1 with viral and host proteins; immunofluorescence localization; IFITM1 knockdown; pharmacological inhibition of cholesterol transport; cholesterol imaging\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple Co-IP partners identified, direct localization at replication sites, KD functional assay, pharmacological rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37252940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM1 and IFITM3 reduce HIV-1 infectivity when incorporated into progeny virions; IFITM3 additionally reduces HIV-1 Env processing and incorporation into virions, whereas IFITM1 does not affect Env clustering (shown by super-resolution imaging).\",\n      \"method\": \"Pseudovirus infectivity assays; super-resolution imaging of Env distribution; Western blot for Env processing\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — super-resolution imaging plus functional infectivity assays; mechanistic distinction between IFITM1 and IFITM3 effects; single lab\",\n      \"pmids\": [\"38140631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oncostatin M induces IFITM1 expression via JAK-STAT signaling (STAT1-IRF9 transcription factor complex), and IFITM1 acts as an HBV restriction factor mediating OSM's anti-HBV activity in vitro and in vivo.\",\n      \"method\": \"RNA-seq; JAK-STAT pathway analysis; HBV replication assays in cells and rAAV8-HBV mice; ELISA\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq-guided mechanism with in vivo validation; single lab\",\n      \"pmids\": [\"37879404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBV core protein (HBc) inhibits IFNα-induced IFITM1 expression by interacting with BAF200, disrupting stability of the PBAF chromatin remodeling complex; basal IFITM1 expression depends on BAF200 rather than the JAK-STAT1 pathway.\",\n      \"method\": \"Yeast two-hybrid; Co-IP in 293T, HepG2 and HepG2-NTCP cells; siRNA knockdown; HBV replication assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP in multiple cell lines with functional antiviral readout; mechanistic dissection of basal vs. IFN-induced IFITM1 regulation; single lab\",\n      \"pmids\": [\"31075894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17A physically interacts with IFITM1 and increases IFITM1 S-palmitoylation by downregulating the depalmitoylase ABHD16A, thereby enhancing IFITM1 antiviral activity; ABHD16A catalyzes depalmitoylation of IFITM1 and negatively regulates its antiviral function.\",\n      \"method\": \"Co-IP; acyl-PEGyl exchange gel-shift (APEGS) palmitoylation assay; siRNA/CRISPR KO; antiviral assays\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct palmitoylation assay with Co-IP and functional antiviral readout; single lab\",\n      \"pmids\": [\"40723864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ABHD16A catalyzes depalmitoylation of IFITM1 and negatively regulates its anti-HBV activity; CRISPR KO of ABHD16A in HepG2.215 cells increases IFITM1 palmitoylation and enhances HBV restriction.\",\n      \"method\": \"Co-IP; APEGS palmitoylation assay; CRISPR/Cas9 KO of IFITM1 and ABHD16A; HBV replication assays\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct palmitoylation assay with CRISPR-based mechanistic validation; single lab\",\n      \"pmids\": [\"40434075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Swine RNF5 ubiquitinates ABHD16A at residues K3 and K452, targeting it for proteasomal degradation; this prevents ABHD16A-mediated depalmitoylation of IFITM1, thereby restoring IFITM1 antiviral activity. This regulatory axis balances antiviral immune responses.\",\n      \"method\": \"AlphaFold2-based PPI prediction; immunofluorescence; Co-IP; ubiquitination assay; site-directed mutagenesis of K3/K452; IFITM1 palmitoylation assay; antiviral assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical ubiquitination assay with mutagenesis and palmitoylation readout; single lab\",\n      \"pmids\": [\"39601593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biochemical characterization of recombinant IFITM1 reveals three conformational variants: monomer, dimer, and highly stable oligomer. The N-terminal region contains a structural motif important for oligomer formation, identified by HDX mass spectrometry and two-site ELISA. Dimer is less stable than oligomer to reducing agents and thermal denaturation.\",\n      \"method\": \"Size exclusion chromatography; circular dichroism thermal denaturation; reducing agent treatment; two-site ELISA; HDX mass spectrometry\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization of recombinant protein with multiple biophysical methods; single lab\",\n      \"pmids\": [\"38379409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFITM1 is predominantly expressed in limbal epithelial stem/early transient amplifying (eTA) cells and positively regulates their proliferation and expansion after corneal wounding via inhibition of OVOL1 (a negative regulator of epithelial cell proliferation). AAV-mediated in vivo IFITM1 knockdown attenuates stem/eTA cell expansion after corneal injury.\",\n      \"method\": \"Single-cell RNA-seq; AAV-mediated in vivo knockdown; IFITM1 overexpression in human limbal epithelial cells; OVOL1 expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo AAV KD with scRNA-seq mechanism; epistasis with OVOL1; single lab\",\n      \"pmids\": [\"40372397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hydroquinone (benzene metabolite) impairs trophoblast migration and invasion via activation of the AhR pathway, which reduces Twist1 and subsequently IFITM1 expression; IFITM1 overexpression rescues impaired trophoblast migration, establishing the AhR-Twist1-IFITM1 axis as a regulator of trophoblast invasion.\",\n      \"method\": \"3D invasion/migration model; AhR pathway activation; Twist1 and IFITM1 qPCR and Western blot; IFITM1 overexpression rescue\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway dissection with rescue experiment; single lab\",\n      \"pmids\": [\"39173312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Invasive FoxM1 phosphorylated at Ser25 by PLK1 upregulates IFITM1 expression through the STING-TBK1-IRF3 signaling axis in lung adenocarcinoma cells with phosphomimetic FoxM1.\",\n      \"method\": \"Immunoprecipitation; LC-MS/MS; kinase assay; site-directed mutagenesis; chromatin immunoprecipitation; microarray analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase assay with mutagenesis and ChIP linking PLK1-FoxM1 to IFITM1 via STING pathway; single lab\",\n      \"pmids\": [\"37968723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PITX2 transcriptionally activates IFITM1, and the resulting PITX2/IFITM1 cascade enhances IFNα-induced AKT activation, mediating letrozole resistance in breast cancer; siRNA ablation of IFITM1 abolishes IFNα-elicited AKT phosphorylation even in PITX2-overexpressing cells.\",\n      \"method\": \"Luciferase transcription assay; siRNA knockdown; AKT phosphorylation assay; xenograft model; Western blot\",\n      \"journal\": \"Cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcription assay plus epistasis knockdown with AKT pathway readout; single lab\",\n      \"pmids\": [\"30025446\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFITM1 is an interferon-stimulated transmembrane protein that restricts diverse viral infections primarily by blocking membrane fusion at the plasma membrane or endosomal compartments; its antiviral breadth and potency are critically regulated by S-palmitoylation on conserved and nonconserved cysteines (written by DHHC enzymes, erased by ABHD16A which is itself regulated by ABHD17A and RNF5-mediated ubiquitination), and by a C-terminal dibasic sorting signal (KRXX) that controls AP-3-dependent subcellular distribution; at the plasma membrane, IFITM1 interacts with caveolin-1 via its transmembrane domains to enhance inhibition of ERK signaling and with tight junction proteins CD81 and occludin to block HCV entry; in the nucleus/cytosol it connects to STAT2/BRG1 and MUC1/STAT1 transcriptional complexes to regulate its own expression; it also associates with SRSF1 and HLA-B mRNA to facilitate ribosomal translation of MHC class I molecules, enabling immune surveillance; in development it acts as a repulsive cue directing primordial germ cell migration via its N-terminal extracellular domain, and in trophoblasts it supports invasion through an AhR-Twist1-IFITM1 axis and limbal stem cell expansion via OVOL1 inhibition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IFITM1 is an interferon-stimulated transmembrane protein with diverse roles in antiviral defense, immune surveillance, cell migration, and proliferation control. Its antiviral activity against HCV, HBV, HIV-1, VSV, and influenza depends on S-palmitoylation of conserved cysteines—written by DHHC enzymes and erased by ABHD16A (itself regulated by ABHD17A and RNF5-mediated ubiquitination)—and on a C-terminal dibasic KRXX sorting signal that governs AP-3-dependent subcellular distribution between plasma membrane and endosomal compartments [PMID:26354436, PMID:25527505, PMID:23804635, PMID:40434075, PMID:39601593]. At the plasma membrane, IFITM1 interacts with caveolin-1 to inhibit ERK signaling and p53 degradation, and with tight-junction proteins CD81 and occludin to block HCV entry; it also associates with SRSF1 and HLA-B mRNA to facilitate ribosomal translation of MHC class I, promoting immune surveillance including complement C3-mediated microglial activation and CD8+ T cell cytotoxicity against metastatic tumor cells [PMID:22996292, PMID:19499152, PMID:36008984, PMID:36799040]. In development, mouse IFITM1 acts as a repulsive cue directing primordial germ cell migration via its N-terminal extracellular domain, and in adult tissues it regulates trophoblast invasion and limbal stem cell expansion [PMID:16326387, PMID:37434700, PMID:40372397].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"The initial discovery that IFITM1 binds RNA and inhibits HIV-1 Rev-dependent post-transcriptional gene expression established it as an interferon-induced antiviral effector, but left its mechanism of action and breadth of viral targets unknown.\",\n      \"evidence\": \"cDNA library screen for RRE-binding proteins with in vitro RNA-binding and HIV-1 expression assays in human cells\",\n      \"pmids\": [\"7680491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding activity not confirmed by orthogonal methods\", \"unclear whether antiviral effect requires direct RNA binding or operates via another mechanism\", \"breadth of viral targets untested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Constitutive expression showed IFITM1 has intrinsic antiviral activity against VSV (but not influenza) and localizes like cytoskeleton-associated proteins, indicating virus-specific restriction independent of the broader IFN response.\",\n      \"evidence\": \"Constitutive cDNA expression in mouse cells with viral plaque assays and immunofluorescence\",\n      \"pmids\": [\"8727077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of VSV restriction unresolved\", \"apparent lack of influenza restriction later contradicted for mouse IFITM1 orthologue\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that mouse Ifitm1 directs primordial germ cell migration via a repulsive mechanism mediated by its N-terminal extracellular domain revealed a developmental function entirely distinct from antiviral activity.\",\n      \"evidence\": \"Mouse genetic loss-of-function and domain-swap experiments with in vivo PGC migration assays\",\n      \"pmids\": [\"16326387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular receptor for IFITM1 repulsive signal unknown\", \"whether human IFITM1 retains PGC guidance function untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mechanistic dissection in hepatocytes showed IFITM1 mediates IFN-γ antiproliferative signaling by inhibiting ERK, enhancing p53 transcriptional activity, and stabilizing p53 through inhibition of Thr55 phosphorylation, establishing a tumor-suppressive signaling role.\",\n      \"evidence\": \"Overexpression/siRNA knockdown with ERK activity, p53 reporter, phospho-p53 assays, and nude mouse tumorigenicity\",\n      \"pmids\": [\"16847454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct biochemical target linking IFITM1 to ERK inhibition not identified\", \"generalizability beyond hepatocytes unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The finding that IFITM1 localizes to caveolae and physically interacts with caveolin-1 via its transmembrane domains to enhance ERK inhibition provided a molecular platform for its antiproliferative signaling.\",\n      \"evidence\": \"Co-IP with deletion mutagenesis, immunofluorescence co-localization, and ERK phosphorylation assay\",\n      \"pmids\": [\"19499152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"stoichiometry and structural basis of IFITM1-CAV1 interaction unknown\", \"single lab without reciprocal Co-IP validation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of IFITM1 as a tight-junction protein interacting with HCV co-receptors CD81 and occludin established that its anti-HCV activity operates by disrupting viral entry at the plasma membrane, validated in patient liver during IFN therapy.\",\n      \"evidence\": \"Reciprocal Co-IP with CD81/occludin, immunofluorescence at tight junctions, HCV entry assay, and patient liver immunohistochemistry\",\n      \"pmids\": [\"22996292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"precise stoichiometry or structural basis of CD81/occludin disruption unknown\", \"whether other tight-junction-tropic viruses are affected untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two studies resolved key post-translational regulatory mechanisms: palmitoylation of conserved cysteines is essential for antiviral activity and protein stability, while the C-terminal KRXX dibasic motif controls AP-3-dependent trafficking between plasma membrane and endosomal compartments, tuning antiviral breadth.\",\n      \"evidence\": \"Palmitoylation assay with cysteine mutagenesis and influenza assay; SCAM topology mapping, AP-3 Co-IP, and mutagenesis with pseudovirus assays\",\n      \"pmids\": [\"23804635\", \"25527505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"identity of DHHC palmitoyltransferase(s) writing IFITM1 palmitoylation not determined\", \"dual topology not yet integrated into structural model\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The C-terminal 9 residues of human IFITM1 were shown to suppress antiviral restriction of HIV-1 by controlling localization; independently, HIV-1 evolved resistance via Vpu/Env mutations enhancing cell-to-cell transmission, defining an evolutionary arms race.\",\n      \"evidence\": \"C-terminal deletion mutagenesis with HIV-1 entry assay; serial passage/whole-genome sequencing with transmission assays\",\n      \"pmids\": [\"25738301\", \"24725927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis for C-terminal autoinhibition unresolved\", \"Vpu stop-codon mechanism not fully understood\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmation that palmitoylation is essential for anti-HCV activity and that IFITM1 localizes to tight junctions/plasma membrane to block HCV entry unified the palmitoylation and tight-junction interaction models.\",\n      \"evidence\": \"Palmitoylation inhibition and mutagenesis with HCV entry/replication assays and confocal localization\",\n      \"pmids\": [\"26354436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"which specific palmitoylation sites are most critical for HCV restriction not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies expanded IFITM1 beyond antiviral restriction: a distal IFN-responsive enhancer was shown to coordinate IFITM locus expression via STAT1-dependent chromatin looping; SWATH-IP proteomics identified ISG15 and HLA-B as major IFITM1-associated proteins; and IFITM1 KO in hESCs derepressed endogenous retroviruses with loss of H3K9me3, revealing epigenetic regulatory capacity.\",\n      \"evidence\": \"ChIP, 3C, CRISPR enhancer deletion with influenza assay; SWATH-IP MS with PLA and CRISPR double-KO; CRISPR IFITM1 KO in hESCs with qRT-PCR and H3K9me3 ChIP\",\n      \"pmids\": [\"28511927\", \"30951861\", \"28781951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking IFITM1 to H3K9 methyltransferase recruitment unknown\", \"functional consequence of ISG15 association for antiviral activity untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The transcriptional regulation of IFITM1 was further elaborated: MUC1-STAT1 interaction drives IFITM1 expression in breast cancer, BAF200/PBAF chromatin remodeling controls basal expression in hepatocytes, and HBV core protein antagonizes IFITM1 induction by destabilizing PBAF.\",\n      \"evidence\": \"Co-IP of MUC1-STAT1 with siRNA/drug in tumor models; yeast two-hybrid and Co-IP of HBc-BAF200 with siRNA and HBV replication assays\",\n      \"pmids\": [\"30655323\", \"31075894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct STAT1 binding sites in IFITM1 promoter for MUC1-dependent activation not mapped\", \"whether PBAF disruption by HBc is specific to IFITM1 or affects other ISGs\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The mechanism by which IFITM1 promotes MHC class I surface expression was resolved: IFITM1 associates with splicing factor SRSF1 and HLA-B mRNA in the cytosol, facilitating ribosomal translation without altering mRNA levels, as demonstrated by ribosome profiling showing reduced 80S fraction in IFITM1/3-null cells.\",\n      \"evidence\": \"SBP-tagged pulldown/MS, RNA-protein PLA, ribosome profiling by sucrose gradient, isogenic CRISPR rescue\",\n      \"pmids\": [\"36008984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"specificity for HLA-B vs. other mRNAs not fully defined\", \"structural basis of IFITM1-SRSF1-mRNA ternary complex unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple discoveries broadened IFITM1 biology: it mediates immune surveillance of brain-metastatic cells via C3 secretion and MHC-I upregulation; it enhances non-enveloped Aichi virus replication by facilitating cholesterol transport to the Golgi; and it reduces extracellular vesicle uptake in colorectal cancer cells.\",\n      \"evidence\": \"In vivo CRISPR screen with C3/MHC-I/T cell assays; Co-IP of IFITM1 with ACBD3/PI4KB/OSBP, cholesterol imaging; organoid IFITM1 KD with EV uptake quantification\",\n      \"pmids\": [\"36799040\", \"37252940\", \"34609520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism by which IFITM1 promotes C3 secretion unknown\", \"proviral cholesterol transport role potentially contradicts canonical antiviral paradigm—generalizability unclear\", \"EV uptake mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The palmitoylation cycle was mechanistically resolved: ABHD16A was identified as the depalmitoylase of IFITM1, and RNF5 ubiquitinates ABHD16A at K3/K452 for proteasomal degradation, creating a ubiquitin-palmitoylation regulatory circuit that tunes antiviral potency. Biophysical characterization also revealed IFITM1 forms monomers, dimers, and highly stable oligomers with N-terminal region involvement.\",\n      \"evidence\": \"Co-IP, APEGS palmitoylation assay, CRISPR KO of ABHD16A with HBV assays; ubiquitination assay with K→R mutagenesis; SEC, CD, HDX-MS of recombinant IFITM1\",\n      \"pmids\": [\"40434075\", \"39601593\", \"38379409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether RNF5-ABHD16A axis operates in human cells (studied in swine)\", \"functional significance of oligomeric states for antiviral activity or signaling unknown\", \"identity of DHHC writer enzymes for IFITM1 still not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ABHD17A was shown to physically interact with IFITM1 and enhance its palmitoylation by downregulating ABHD16A, adding another layer to the palmitoylation regulatory network; separately, IFITM1 was identified as a regulator of limbal epithelial stem cell expansion via OVOL1 inhibition after corneal injury.\",\n      \"evidence\": \"Co-IP and APEGS palmitoylation assay with antiviral assays; scRNA-seq with AAV-mediated in vivo KD and OVOL1 epistasis\",\n      \"pmids\": [\"40723864\", \"40372397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ABHD17A mechanism of ABHD16A downregulation not fully elucidated\", \"OVOL1 inhibition mechanism (direct or indirect) not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of IFITM1 membrane fusion inhibition, the identity of DHHC palmitoyltransferases that write IFITM1 palmitoylation, the molecular receptor mediating its developmental repulsive cue, reconciliation of proviral (Aichi virus) versus antiviral roles, and whether oligomeric states have distinct functional outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no high-resolution structure of IFITM1 in membrane context\", \"DHHC writer enzymes unidentified\", \"proviral vs. antiviral duality mechanism unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 12, 22]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 23]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 6, 7, 9, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7, 27]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 6, 8, 9, 15, 25, 28, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 5, 20, 38]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 16, 30]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 26, 36]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 9, 31, 32, 33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 14, 21, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CAV1\",\n      \"CD81\",\n      \"OCLN\",\n      \"SRSF1\",\n      \"ABHD16A\",\n      \"ABHD17A\",\n      \"ACBD3\",\n      \"AP3B1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}