{"gene":"IFITM1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1993,"finding":"The IFITM1 protein (encoded by the interferon-inducible 9-27 gene) binds RNA in vitro and inhibits HIV-1 expression by blocking Rev-dependent post-transcriptional steps of viral gene expression when transfected into human cells.","method":"cDNA library screen for RRE-binding proteins, in vitro RNA-binding assay, transfection with HIV-1 expression assay","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro RNA-binding assay plus functional transfection assay in human cells; single lab but two orthogonal methods","pmids":["7680491"],"is_preprint":false},{"year":1996,"finding":"IFITM1 (9-27 protein) has intrinsic antiviral activity against vesicular stomatitis virus (VSV) but not influenza virus; its intracellular distribution resembles that of cytoskeleton-associated proteins.","method":"Constitutive expression of 9-27 cDNA in mouse cells, indirect immunofluorescence, single-cell virus resistance assay","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with functional virus assay and localization imaging, single lab","pmids":["8727077"],"is_preprint":false},{"year":1998,"finding":"The rat ortholog of IFITM1 (rat8/9-27 homolog) is required for dome formation in mammary epithelial cells; antisense suppression abolishes dome formation, while forced expression in non-dome-forming cells induces morphological changes suggesting tightened lateral cell connections; the gene is expressed in epithelial tubular structures.","method":"Subtractive cDNA library, antisense treatment, forced overexpression, in situ hybridization","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (antisense) and gain-of-function (overexpression) with defined cellular phenotype, single lab","pmids":["9448288"],"is_preprint":false},{"year":2005,"finding":"Mouse IFITM1 mediates repulsion of primordial germ cells (PGCs) from the posterior mesoderm into the endoderm via a repulsive mechanism; this activity requires the N-terminal extracellular domain of IFITM1, which cannot be substituted by another IFITM family member's N-terminal domain.","method":"Loss-of-function experiments in mouse embryos, domain-swap/chimeric protein analysis, PGC migration tracking","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined PGC phenotype, domain-specificity established by chimeric protein, two orthogonal approaches, replicated in same study","pmids":["16326387"],"is_preprint":false},{"year":2006,"finding":"IFITM1 is required downstream of STAT1 for IFN-γ-mediated antiproliferative effects; IFITM1 overexpression inhibits ERK activity, enhances p53 transcriptional activity, and stabilizes p53 by preventing phosphorylation at Thr55; knockdown of IFITM1 blocks IFN-γ antiproliferative activity and confers tumorigenicity to non-malignant hepatocytes.","method":"Overexpression and siRNA knockdown of IFITM1, ERK activity assay, p53 transcriptional reporter assay, phosphorylation analysis, nude mouse tumorigenicity assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function (siRNA) and gain-of-function (overexpression) with multiple downstream pathway readouts (ERK, p53 phosphorylation, transcription), in vitro and in vivo validation, single lab with multiple orthogonal methods","pmids":["16847454"],"is_preprint":false},{"year":2009,"finding":"IFITM1 localizes to caveolae of the plasma membrane and physically interacts with caveolin-1 (CAV-1) through its hydrophobic transmembrane domains; this interaction enhances CAV-1's inhibitory effect on ERK phosphorylation, without IFITM1 directly activating ERK.","method":"Immunofluorescence, co-immunoprecipitation, deletion mutagenesis, ERK phosphorylation assay, siRNA knockdown of CAV-1","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mutagenesis plus 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 (but not p38, JNK, or PKC); cross-linking of IFITM1 with a monoclonal antibody induces expression of proinflammatory mediators IL-8 and MMP-9 in THP-1 macrophages.","method":"Pathway inhibitors (ERK, PI3K, NF-κB, p38, JNK, PKC), RT-PCR, Western blot, antibody cross-linking of IFITM1","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitors plus direct IFITM1 cross-linking functional assay; multiple inhibitors tested, single lab","pmids":["20847954"],"is_preprint":false},{"year":2011,"finding":"Exogenous expression of IFITM1 inhibits HCV replication in immortalized human hepatocytes (IHH) and Huh7 cells, and knockdown enhances HCV replication; IFITM1 overexpression does not block HCV pseudotype entry, suggesting action at a post-entry step.","method":"Overexpression and siRNA knockdown in IHH and Huh7 cells, HCV replication assay, HCV pseudotype entry assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional loss- and gain-of-function with both replication and entry assays in two cell lines, single lab","pmids":["21976647"],"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-immunoprecipitation (IFITM1 with CD81 and occludin), immunofluorescence/confocal microscopy of tight junction localization, patient liver biopsy immunostaining, functional HCV entry assays","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying binding partners, subcellular localization confirmed in cell lines and patient tissue, functional viral entry assay, multiple orthogonal methods","pmids":["22996292"],"is_preprint":false},{"year":2013,"finding":"IFITM1 restricts virus entry and its intracellular distribution is governed by a C-terminal non-canonical dibasic sorting signal (KRXX); mutating the two basic residues (KR/AA) increases restriction of jaagsiekte sheep retrovirus (JSRV) and amphotropic MLV by altering distribution toward CD63+ multivesicular bodies and away from LAMP1+ lysosomes; IFITM1 binds adaptor protein complex 3 (AP-3), and this association is lost when the dibasic motif is mutated; IFITM1 adopts more than one membrane topology co-existing in cellular membranes.","method":"Site-directed mutagenesis of KRXX motif, deconvolution microscopy, co-immunoprecipitation with AP-3, AP-3 knockdown, substituted cysteine accessibility method (SCAM) for topology","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis plus Co-IP plus structural topology assay (SCAM) plus microscopy, multiple orthogonal methods in single rigorous study","pmids":["25527505"],"is_preprint":false},{"year":2013,"finding":"S-palmitoylation of IFITM1 on conserved and non-conserved cysteines is required for anti-influenza A virus activity; palmitoylation also prevents proteasomal degradation of IFITM1; palmitoylation of the nonconserved C-terminal cysteine supports an intramembrane topology.","method":"Palmitoylation assays, site-directed cysteine mutagenesis, proteasome inhibitor treatment, influenza A virus infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific cysteines combined with palmitoylation assay, protein stability assay, and functional antiviral readout; multiple orthogonal methods","pmids":["23804635"],"is_preprint":false},{"year":2013,"finding":"S-palmitoylation of all three IFITM proteins (including IFITM1) is essential for anti-HCV activity; the conserved tyrosine residue in the N-terminal domain of IFITM1 is dispensable for anti-HCV activity (in contrast to IFITM2/3 where it regulates localization); IFITM2/3 localize to late and early endosomes and lysosomes in hepatocytes, while IFITM1 co-localizes with CD81.","method":"S-palmitoylation assays, site-directed mutagenesis of cysteines and tyrosine residues, HCV entry and replication assays, subcellular co-localization immunofluorescence","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — palmitoylation mutagenesis linked to antiviral function, tyrosine mutant phenotype localization assay, multiple orthogonal methods","pmids":["26354436"],"is_preprint":false},{"year":2013,"finding":"IFITM-1 does not restrict Rift Valley fever virus (RVFV) infection, while IFITM-2 and IFITM-3 do; IFITM-1 occupies vesicular compartments distinct from those occupied by IFITM-2 and -3.","method":"Overexpression of individual IFITMs, viral infection assays with RVFV, vesicle compartment imaging","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with direct viral restriction assay and subcellular compartment imaging; negative result for IFITM1 vs RVFV is mechanistically informative about virus specificity","pmids":["23720721"],"is_preprint":false},{"year":2014,"finding":"HIV-1 can mutate to evade IFITM1 restriction; mutations in vpu (Vpu34, introducing a premature stop) and env (EnvG367E at the CD4-binding site of gp120) together enable HIV-1 replication in IFITM1-expressing cells by promoting cell-to-cell virus transmission rather than overcoming IFITM1-mediated downregulation of p24 expression.","method":"Serial passage of HIV-1 in IFITM1-expressing SupT1 cells, full genome sequencing, mutant virus functional assays, cell-to-cell transmission assay","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — serial passage selection with genetic identification and functional validation of viral mutations; single lab","pmids":["24725927"],"is_preprint":false},{"year":2014,"finding":"IFITM1 does not inhibit infection by HPV16, human cytomegalovirus (HCMV), or adenovirus type 5; IFITM1 and IFITM3 modestly enhanced HPV16 infection in multiple cell types including primary keratinocytes.","method":"Overexpression in multiple cell types including primary keratinocytes, viral infection assays for HPV16, HCMV, and Ad5","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression functional assay across multiple cell types and three DNA viruses; finding is a negative result for restriction but a positive finding for modest HPV enhancement","pmids":["24827144"],"is_preprint":false},{"year":2015,"finding":"The C-terminal 9 amino acids of IFITM1 contain a sorting signal that suppresses anti-HIV-1 activity; deletion of residues 117–125 (Δ117-125) relocates IFITM1 predominantly to the plasma membrane where HIV-1 entry occurs and enables 3-fold inhibition of HIV-1 entry; wild-type human IFITM1 (which has a longer C-terminus compared to mouse IFITM1) does not inhibit HIV-1 entry.","method":"C-terminal deletion mutagenesis, subcellular localization imaging, HIV-1 entry assay, comparison of human vs. mouse IFITM1","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with localization imaging and functional entry assay; single lab","pmids":["25738301"],"is_preprint":false},{"year":2015,"finding":"IFITM1 loss of function in AI-resistant MCF-7:5C cells markedly increases p21 transcription, expression, and nuclear localization mediated by JAK/STAT activation; IFITM1 overexpression in wild-type MCF-7 cells promotes estrogen-independent growth.","method":"Lentivirus shRNA knockdown, overexpression, orthotopic and MIND mouse models, p21 reporter assays, JAK/STAT inhibition","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional loss/gain-of-function with in vivo model and mechanistic p21/JAK-STAT pathway assays; single lab","pmids":["28411130"],"is_preprint":false},{"year":2016,"finding":"IFITM1 promotes CRC cell migration/invasion through a mechanism involving CAV-1 as a downstream target; knockdown of CAV-1 abrogates IFITM1-siRNA-mediated inhibition of cell invasion, placing CAV-1 downstream of IFITM1 in a pro-invasive pathway.","method":"Overexpression and siRNA knockdown of IFITM1, siRNA knockdown of CAV-1, migration/invasion assays, epistasis rescue experiment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (rescue assay) placing CAV-1 downstream of IFITM1, single lab","pmids":["27852071"],"is_preprint":false},{"year":2016,"finding":"IFITM1 overexpression in SUM149 IBC cells promotes aggressiveness in a STAT2-dependent manner; STAT2 knockdown abolishes IFITM1 expression and IFITM1 promoter activity; STAT2-mediated IFITM1 activation is dependent on the chromatin remodeler BRG1.","method":"siRNA/shRNA knockdown of IFITM1, STAT1/2, and BRG1; luciferase promoter assays; migration, invasion, and colony formation assays","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase promoter assay plus knockdown of upstream regulators plus functional phenotypic readouts; single lab with multiple orthogonal methods","pmids":["26897526"],"is_preprint":false},{"year":2017,"finding":"An IFN-responsive enhancer located 35 kb upstream of IFITM3 coordinately upregulates IFN-induced expression of IFITM1, IFITM2, and IFITM3 genes; STAT1 binds this enhancer upon IFN treatment; chromatin looping brings the IFITM gene cluster into physical contact with this distal enhancer; in vivo truncation of the enhancer impairs IFN-induced resistance to influenza A virus.","method":"Luciferase reporter assay, CRISPR-Cas9 genome editing (in vivo enhancer truncation), ChIP assay, EMSA, 3C (chromosome conformation capture)","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, EMSA, 3C, CRISPR in vivo deletion) with functional antiviral readout; rigorous study","pmids":["28511927"],"is_preprint":false},{"year":2017,"finding":"HPV infection downregulates IFITM1 expression; knockdown of IFITM1 in uninfected keratinocytes confirms its role in IFN-γ/TNF-α-mediated antiproliferative effects and in regulating RARRES1 expression.","method":"siRNA knockdown of IFITM1, cell growth/proliferation assays, gene expression analysis, S-phase arrest analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with downstream gene and proliferation readout, single lab","pmids":["27920775"],"is_preprint":false},{"year":2017,"finding":"IFITM1 suppresses expression of human endogenous retroviruses (HERVs) in human embryonic stem cells (hESCs) by regulating epigenetic modifications; IFITM1 knockout (CRISPR/Cas9) increases HERV expression and reduces trimethylation of H3K9 at HERV loci.","method":"CRISPR/Cas9 knockout of IFITM1 in hESCs, HERV expression analysis, H3K9me3 ChIP at HERV loci","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with epigenetic readout at specific loci, single lab","pmids":["28781951"],"is_preprint":false},{"year":2019,"finding":"G3BP1 and G3BP2 RNA-binding proteins are essential for the accumulation of IFITM1 protein and regulate IFITM1 expression through both the MEK pathway and interaction with the 3'-UTR of IFITM1 transcripts.","method":"G3BP knockdown, MEK pathway inhibition, 3'-UTR interaction assays, Western blot of IFITM protein levels","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, G3BP knockdown with protein level readout, 3'-UTR interaction assay not fully characterized by method in abstract","pmids":["31172368"],"is_preprint":false},{"year":2019,"finding":"IFITM1 and IFITM3 double knockout in cervical cancer cells attenuates IFNγ-stimulated synthesis of IRF1, HLA-B, and ISG15; SBP-tagged IFITM1 co-associates with ISG15 and HLA-B by SWATH-IP mass spectrometry; HLA-B interacts with IFITM1/3 by proximity ligation assay; ISG15ylation is attenuated in IFITM1/IFITM3 double-null cells; IFITM1-targeted siRNA attenuates an IFN-regulated protein subpopulation including MHC Class I molecules.","method":"CRISPR-Cas9 double KO, pulse SILAC, SWATH-IP mass spectrometry, proximity ligation assay, siRNA knockdown","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (CRISPR KO, SILAC, MS, PLA), single lab","pmids":["30951861"],"is_preprint":false},{"year":2019,"finding":"MUC1 interacts with STAT1 via JAK/STAT signaling to drive IFITM1 transcription; knockdown of MUC1 by siRNA or pharmacological inhibitors abrogates IFITM1 mRNA and protein expression; in vivo, estrogen and ruxolitinib reduce MUC1, P-STAT1, and IFITM1 expression.","method":"siRNA knockdown of MUC1, pharmacological inhibitors, Western blot, in vivo mouse model with ruxolitinib treatment","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA and inhibitor) with defined downstream IFITM1 expression readout, in vivo validation, single lab","pmids":["30655323"],"is_preprint":false},{"year":2019,"finding":"HBV core protein (HBc) inhibits IFNα-induced IFITM1 expression by interacting with BAF200 (a component of the PBAF chromatin remodeling complex); basal IFITM1 expression depends on BAF200, not the JAK-STAT1 pathway; HBc-BAF200 interaction disrupts PBAF complex stability and suppresses IFITM1 transcription.","method":"Yeast two-hybrid, co-immunoprecipitation (HBc-BAF200 interaction), Western blot, HBV replication assay, co-transfection rescue experiments","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, mechanistic rescue experiment, multiple cell lines; single lab","pmids":["31075894"],"is_preprint":false},{"year":2019,"finding":"NF-κB and IRF1 transcription factors bind an enhancer region (R2, 2 kb upstream) of the IFITM1 gene to mediate LPS-stimulated IFITM1 expression and hMSC migration; LPS treatment increases enhancer RNA expression at R2 and H3K27ac enrichment at R2; knockdown of IFITM1 impairs LPS-stimulated cell migration.","method":"ChIP sequencing, ChIP-PCR, luciferase reporter assay, qRT-PCR for enhancer RNAs, RNAi (NF-κB and IRF1), wound healing assay","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (ChIP-seq, luciferase, RNAi), single lab","pmids":["31910882"],"is_preprint":false},{"year":2021,"finding":"IFITM1 expression determined by APC/Wnt signaling controls extracellular vesicle (EV) uptake in colorectal cancer; APC mutation induces IFITM1 expression; IFITM1high CRC cells show markedly reduced uptake of fibroblast EVs; inactivation of IFITM1 enhances EV uptake.","method":"Mouse and patient-derived organoids, APC mutation models, IFITM1 knockout/knockdown, EV uptake assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (IFITM1 inactivation) with functional EV uptake assay in organoid models, single lab","pmids":["34609520"],"is_preprint":false},{"year":2021,"finding":"NF-κB is an important downstream target of IFITM1 in TNBC; siRNA/CRISPR KO of IFITM1 inhibits proliferation, colony formation, and wound healing in vitro and reduces tumor growth/invasion in vivo; RNA-seq of IFITM1 KO cells reveals downregulation of genes involved in proliferation, migration, and invasion.","method":"siRNA and CRISPR/Cas9 knockout, RNA-seq, orthotopic and MIND mouse models, NF-κB siRNA rescue experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with RNA-seq pathway analysis and in vivo validation, single lab","pmids":["34022283"],"is_preprint":false},{"year":2022,"finding":"IFITM1 associates with the splicing factor SRSF1 (predominantly in the cytosol); IFITM1/3 interact with HLA-B mRNA in response to IFNγ; IFITM1/3 double KO cells show a reduction in the 80S ribosomal fraction; loss of IFITM1/3 reduces HLA-B protein synthesis without affecting HLA-B mRNA levels, placing IFITM1 function at the translational rather than transcriptional level for HLA-B.","method":"SBP-tagged IFITM1 pulldown/MS, proximity ligation assay (protein-protein and RNA-protein), ribosome profiling by sucrose gradient sedimentation, RT-qPCR, RNA-seq","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (PLA, ribosome profiling, RNA-protein interaction), single lab","pmids":["36008984"],"is_preprint":false},{"year":2023,"finding":"IFITM1 high expression in incipient brain metastatic lung cancer cells mediates immune surveillance by: secreting complement component C3 to activate microglia and by increasing MHC class I surface expression to enhance CD8+ T cell cytolytic activity; loss of IFITM1 promotes brain colonization by escaping both innate (microglia phagocytosis) and adaptive (CD8+ T cell killing) immune responses.","method":"In vivo genome-wide CRISPR-Cas9 screen, IFITM1 overexpression/knockdown, co-culture assays, MHC-I surface expression assays, C3 secretion measurement, CD8+ T cell killing assay, PD-1 blockade mouse model","journal":"EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen validated by multiple functional assays (immune cell killing, phagocytosis, MHC-I surface expression, C3 secretion) in vitro and in vivo; single lab but rigorous with multiple orthogonal readouts","pmids":["36799040"],"is_preprint":false},{"year":2023,"finding":"IFITM1 facilitates cholesterol transport from late endosomes to the Golgi, which is exploited by Aichi virus (a non-enveloped RNA virus) to form cholesterol-rich replication sites; IFITM1 localizes to viral RNA replication sites; IFITM1 interacts with viral proteins and host Golgi proteins ACBD3, PI4KB, and OSBP at replication sites; IFITM1 knockdown significantly reduces AiV RNA replication.","method":"siRNA knockdown, overexpression, co-immunoprecipitation (IFITM1 with ACBD3, PI4KB, OSBP), fluorescence imaging of cholesterol distribution, pharmacological inhibition of ER-Golgi cholesterol transport","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional knockdown plus cholesterol imaging; single lab with multiple orthogonal methods","pmids":["37252940"],"is_preprint":false},{"year":2023,"finding":"IFN-β-induced IFITM1 upregulation impairs extravillous cytotrophoblast (EVCT) invasion; transduction of IFITM1 into trophoblast cells directly reduces invasive ability; IFITM1 is upregulated in CMV- and bacterially infected human placentas.","method":"In vitro/ex vivo EVCT invasion assays, IFITM1 transduction (lentiviral), in vivo poly(I:C) mouse model, human pathological placenta immunostaining","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function (transduction) with defined cellular invasion phenotype, confirmed in vivo mouse model and human tissue; single lab","pmids":["37434700"],"is_preprint":false},{"year":2023,"finding":"IFITM1 is upregulated in invasive lung adenocarcinoma (LUAD) with phosphomimetic FoxM1 (phosphorylated at Ser25 by PLK1) through activation of the STING-TBK1-IRF3 signaling pathway.","method":"Immunoprecipitation, kinase assay, site-directed mutagenesis, chromatin immunoprecipitation, microarray analysis, LC-MS/MS","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, kinase assay, and mutagenesis linking PLK1-FoxM1-STING pathway to IFITM1 induction; single lab, multiple methods","pmids":["37968723"],"is_preprint":false},{"year":2025,"finding":"ABHD17A physically interacts with IFITM1 and paradoxically increases its S-palmitoylation level (and thereby antiviral activity) not by directly palmitoylating it, but by downregulating the depalmitoylase ABHD16A; ABHD16A catalyzes depalmitoylation of IFITM1 and negatively regulates its antiviral activity, and ABHD17A counteracts this by suppressing ABHD16A.","method":"Co-immunoprecipitation, acyl-PEG exchange gel-shift palmitoylation assay, ABHD16A knockdown/overexpression, antiviral activity assays","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with palmitoylation assay and functional antiviral readout; single lab, multiple orthogonal methods","pmids":["40723864"],"is_preprint":false},{"year":2025,"finding":"ABHD16A catalyzes depalmitoylation of IFITM1 in HepG2.215 cells and negatively regulates its anti-HBV activity; CRISPR/Cas9 knockout of ABHD16A enhances IFITM1-mediated restriction of HBV replication; the anti-HBV activity of IFITM1 depends on palmitoylation modification.","method":"Co-immunoprecipitation, acyl-PEGyl exchange gel-shift assay (APEGS), CRISPR/Cas9 knockout of IFITM1 and ABHD16A, HBV replication assay","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — palmitoylation assay plus CRISPR KO with functional viral replication readout, single lab","pmids":["40434075"],"is_preprint":false},{"year":2025,"finding":"IFITM1 promotes VSMC proliferation, migration, and macrophage-like transdifferentiation via the c-Src/MAPK/GATA2/E2F2 signaling pathway; overexpression of IFITM1 upregulates p-Src, p-p38 MAPK, p-GATA2, and E2F2 levels; in vivo overexpression accelerates atherosclerotic plaque formation in ApoE-/- mice.","method":"RNA sequencing, Western blot (pathway intermediates), cell viability/flow cytometry/wound healing/transwell assays, ApoE-/- mouse model, IFITM1 overexpression","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pathway intermediate measurements and in vivo plaque model; single lab, multiple orthogonal methods","pmids":["40466954"],"is_preprint":false},{"year":2025,"finding":"IFITM1 promotes limbal epithelial stem/early transient amplifying (eTA) cell expansion after corneal wounding partly through inhibition of OVOL1, a negative regulator of epithelial cell proliferation; in vivo AAV-mediated knockdown of IFITM1 significantly attenuates stem/eTA cell expansion and activation after corneal injury.","method":"Single-cell RNA sequencing, AAV-mediated in vivo IFITM1 knockdown, human limbal epithelial cell proliferation assays, OVOL1 pathway analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV KD plus in vitro proliferation assay with pathway (OVOL1) analysis; single lab","pmids":["40372397"],"is_preprint":false}],"current_model":"IFITM1 is an interferon-induced transmembrane protein that restricts entry of diverse enveloped RNA viruses (acting at endosomal/tight-junction stages) and some non-enveloped viruses (by facilitating cholesterol trafficking to replication sites), with its antiviral and cellular functions critically dependent on S-palmitoylation of conserved cysteines (regulated by writers such as DHHC enzymes and erasers ABHD16A/ABHD17A), while in non-viral contexts it mediates IFN-γ antiproliferative signaling downstream of STAT1 by inhibiting ERK through CAV-1 interaction and stabilizing p53, governs primordial germ cell repulsion via its N-terminal extracellular domain, promotes or suppresses tumor cell invasion depending on cancer context (often through CAV-1 and NF-κB downstream), facilitates MHC class I surface expression and immune surveillance of metastatic cells, and is transcriptionally regulated by STAT1/STAT2 binding to a distal IFN-responsive enhancer via long-range chromatin looping."},"narrative":{"mechanistic_narrative":"IFITM1 is an interferon-induced transmembrane protein that restricts entry and replication of diverse viruses while also serving as a signaling and developmental effector in non-viral contexts [PMID:8727077, PMID:16847454, PMID:22996292]. As an antiviral restriction factor, IFITM1 blocks vesicular stomatitis virus and acts at post-entry or entry steps against HCV, where it localizes to hepatocyte tight junctions and physically interacts with the HCV co-receptors CD81 and occludin to disrupt viral entry [PMID:8727077, PMID:21976647, PMID:22996292]. Its antiviral activity and protein stability depend critically on S-palmitoylation of conserved cysteines, which is countered by the depalmitoylase ABHD16A and indirectly enhanced by ABHD17A through suppression of ABHD16A [PMID:23804635, PMID:40723864, PMID:40434075]. IFITM1 intracellular distribution and membrane topology are governed by a C-terminal non-canonical dibasic (KRXX) sorting signal that binds adaptor protein complex AP-3, directing the protein among endosomal compartments and the plasma membrane and thereby tuning which viruses it restricts [PMID:25527505, PMID:25738301]. Distinct from restriction, IFITM1 can facilitate cholesterol transport from late endosomes to the Golgi, a function exploited by the non-enveloped Aichi virus to build cholesterol-rich replication sites, where IFITM1 associates with ACBD3, PI4KB, and OSBP [PMID:37252940]. In non-viral signaling, IFITM1 functions downstream of STAT1 to mediate IFN-γ antiproliferative effects by inhibiting ERK—partly through interaction with caveolin-1 at caveolae—and by stabilizing p53 [PMID:16847454, PMID:19499152]. IFITM1 also supports IFN-γ-driven MHC class I expression and immune surveillance of metastatic cells, acting at the translational level to promote HLA-B synthesis and secreting complement C3 to recruit microglia [PMID:30951861, PMID:36008984, PMID:36799040]. In development, IFITM1 mediates repulsion of primordial germ cells via its N-terminal extracellular domain [PMID:16326387]. Its transcription is controlled by STAT1/STAT2 binding to a distal IFN-responsive enhancer engaged through long-range chromatin looping [PMID:28511927]. Across cancers IFITM1 has context-dependent pro- or anti-tumor roles, frequently signaling through CAV-1 and NF-κB [PMID:27852071, PMID:34022283].","teleology":[{"year":1993,"claim":"Established the first functional activity for the interferon-inducible 9-27 protein, framing IFITM1 as an antiviral effector capable of binding RNA and interfering with viral gene expression.","evidence":"cDNA library screen for RRE-binding proteins, in vitro RNA-binding assay, and HIV-1 expression assay after transfection in human cells","pmids":["7680491"],"confidence":"Medium","gaps":["RNA binding shown in vitro only, with unclear physiological relevance","Did not establish whether antiviral effect was direct or via host signaling"]},{"year":1996,"claim":"Demonstrated that IFITM1 has intrinsic, virus-selective antiviral activity (active against VSV, inactive against influenza), establishing virus specificity as a defining feature.","evidence":"Constitutive expression of 9-27 cDNA in mouse cells with single-cell virus resistance assay and immunofluorescence localization","pmids":["8727077"],"confidence":"Medium","gaps":["Mechanistic basis of virus selectivity not defined","Subcellular localization only described qualitatively"]},{"year":1998,"claim":"Linked IFITM1 to epithelial cell-cell junction biology by showing its ortholog is required for dome formation in mammary epithelia, revealing a non-antiviral cellular role.","evidence":"Subtractive cDNA library, antisense suppression, forced overexpression, and in situ hybridization in rat mammary epithelial cells","pmids":["9448288"],"confidence":"Medium","gaps":["Molecular partners at junctions not identified","Used the rat ortholog rather than human IFITM1"]},{"year":2005,"claim":"Defined a developmental function in primordial germ cell repulsion and mapped it to the N-terminal extracellular domain, demonstrating domain-specific, non-antiviral signaling.","evidence":"Loss-of-function in mouse embryos plus domain-swap chimera analysis and PGC migration tracking","pmids":["16326387"],"confidence":"High","gaps":["Receptor/ligand mediating repulsion not identified","Downstream signaling unknown"]},{"year":2006,"claim":"Placed IFITM1 downstream of STAT1 as a required mediator of IFN-γ antiproliferative signaling, connecting it to ERK inhibition and p53 stabilization and to tumor suppression.","evidence":"Overexpression and siRNA knockdown with ERK and p53 reporter/phosphorylation assays and nude mouse tumorigenicity assay","pmids":["16847454"],"confidence":"High","gaps":["Direct molecular target by which IFITM1 inhibits ERK not defined here","Mechanism of p53 Thr55 phosphorylation prevention unresolved"]},{"year":2009,"claim":"Identified caveolin-1 as a physical partner, providing a molecular route by which IFITM1 enhances ERK inhibition without itself being a kinase.","evidence":"Immunofluorescence, co-immunoprecipitation, deletion mutagenesis, ERK phosphorylation assay, and CAV-1 knockdown","pmids":["19499152"],"confidence":"Medium","gaps":["Single-lab interaction without reciprocal validation in multiple systems","How transmembrane-domain binding modulates CAV-1 activity not structurally defined"]},{"year":2010,"claim":"Showed IFITM1 is induced via CD147/cyclophilin A through ERK, PI3K, and NF-κB and can itself drive proinflammatory output, implicating it in inflammatory signaling.","evidence":"Pathway inhibitors, RT-PCR, Western blot, and antibody cross-linking of IFITM1 in THP-1 macrophages","pmids":["20847954"],"confidence":"Medium","gaps":["Cross-linking is a surrogate for natural ligation","Direct downstream effectors of IFITM1 signaling not mapped"]},{"year":2011,"claim":"Established IFITM1 as an anti-HCV factor acting post-entry, distinguishing its mechanism from a pure entry block.","evidence":"Bidirectional overexpression and knockdown in IHH and Huh7 cells with HCV replication and pseudotype entry assays","pmids":["21976647"],"confidence":"Medium","gaps":["Post-entry step not molecularly defined","Apparent tension with later entry-block findings unresolved"]},{"year":2012,"claim":"Localized IFITM1 to hepatocyte tight junctions and identified CD81 and occludin as binding partners, defining an entry-disruption mechanism against HCV relevant in patient tissue.","evidence":"Reciprocal Co-IP, confocal localization in cells and patient liver biopsies, and functional HCV entry assays","pmids":["22996292"],"confidence":"High","gaps":["Whether IFITM1 blocks entry by occluding co-receptors or altering membrane properties not resolved","Reconciliation with the earlier post-entry result not addressed"]},{"year":2013,"claim":"Defined the trafficking and topology determinants of IFITM1: a C-terminal dibasic KRXX motif that binds AP-3 and controls endosomal distribution and restriction breadth, with the protein adopting multiple membrane topologies.","evidence":"Site-directed mutagenesis, deconvolution microscopy, AP-3 Co-IP and knockdown, and SCAM topology mapping","pmids":["25527505"],"confidence":"High","gaps":["Functional consequence of multiple co-existing topologies unknown","How distribution shifts translate into altered restriction mechanistically unclear"]},{"year":2013,"claim":"Identified S-palmitoylation of conserved cysteines as essential for IFITM1 antiviral activity and protein stability, establishing a post-translational switch controlling function.","evidence":"Palmitoylation assays, cysteine mutagenesis, proteasome inhibition, and influenza A and HCV infection assays","pmids":["23804635","26354436"],"confidence":"High","gaps":["Palmitoyltransferases acting on IFITM1 not identified in these studies","Why the N-terminal tyrosine is dispensable for IFITM1 but not IFITM2/3 not mechanistically explained"]},{"year":2013,"claim":"Mapped IFITM1's antiviral specificity by negative results, showing it fails to restrict RVFV, HPV16, HCMV, and Ad5 and even modestly enhances HPV16, refining which viruses it acts upon and where its compartments differ from IFITM2/3.","evidence":"Overexpression of individual IFITMs with viral restriction assays and vesicle compartment imaging across multiple cell types","pmids":["23720721","24827144"],"confidence":"Medium","gaps":["Mechanism of HPV16 enhancement not defined","Compartment differences described but not functionally tested"]},{"year":2014,"claim":"Demonstrated viral evolutionary escape from IFITM1 via vpu and env mutations promoting cell-to-cell spread, illuminating how restriction is countered.","evidence":"Serial passage of HIV-1 in IFITM1-expressing SupT1 cells with genome sequencing and cell-to-cell transmission assays","pmids":["24725927"],"confidence":"Medium","gaps":["Direct molecular interaction between IFITM1 and viral proteins not shown","Generalizability beyond passaged strains uncertain"]},{"year":2015,"claim":"Showed that the C-terminal sorting signal restrains IFITM1 anti-HIV activity by keeping it off the plasma membrane, explaining why human IFITM1 normally fails to block HIV entry.","evidence":"C-terminal deletion mutagenesis, subcellular localization imaging, HIV-1 entry assays, and human vs. mouse comparison","pmids":["25738301"],"confidence":"Medium","gaps":["Effect modest (3-fold) and confined to a deletion mutant","Physiological relevance of relocated IFITM1 unclear"]},{"year":2017,"claim":"Resolved how IFN coordinately induces the IFITM cluster, showing STAT1 binds a distal enhancer that loops to the IFITM genes and is required for antiviral resistance in vivo.","evidence":"Luciferase reporter, ChIP, EMSA, 3C chromosome conformation capture, and CRISPR in vivo enhancer truncation","pmids":["28511927"],"confidence":"High","gaps":["Relative contribution of each IFITM gene to the in vivo phenotype not separated","Looping architecture not resolved at base-pair detail"]},{"year":2017,"claim":"Revealed epigenetic and developmental functions, showing IFITM1 silences HERVs via H3K9me3 and contributes to IFN-γ/TNF-α antiproliferative control of keratinocytes, broadening its non-viral repertoire.","evidence":"CRISPR/Cas9 knockout in hESCs with HERV expression and H3K9me3 ChIP; siRNA knockdown with proliferation and RARRES1 readouts in keratinocytes","pmids":["28781951","27920775"],"confidence":"Medium","gaps":["How a transmembrane protein influences chromatin marks at HERV loci is mechanistically unexplained","Direct versus indirect epigenetic effects not distinguished"]},{"year":2019,"claim":"Diversified IFITM1's expression control, identifying MUC1-STAT1, NF-κB/IRF1 enhancer engagement, BAF200/PBAF for basal expression, and G3BP-dependent protein accumulation as distinct regulatory inputs.","evidence":"siRNA/inhibitor studies, ChIP-seq and luciferase enhancer assays, yeast two-hybrid and Co-IP, and 3'-UTR interaction assays across cell models","pmids":["30655323","31910882","31075894","31172368"],"confidence":"Medium","gaps":["G3BP regulation rests on incompletely characterized methods (Low confidence)","Hierarchy among these regulatory inputs in a single cell type unresolved"]},{"year":2019,"claim":"Connected IFITM1 to MHC class I immune surveillance, showing IFITM1/3 are needed for IFN-γ-stimulated HLA-B and ISG15 synthesis and associate with ISG15 and HLA-B.","evidence":"CRISPR double KO, pulse SILAC, SWATH-IP mass spectrometry, proximity ligation, and siRNA in cervical cancer cells","pmids":["30951861"],"confidence":"Medium","gaps":["Whether interactions are direct not established by PLA alone","Step in HLA-B production affected not yet defined here"]},{"year":2022,"claim":"Localized IFITM1's role in HLA-B production to translation, showing it interacts with SRSF1 and HLA-B mRNA and that its loss reduces HLA-B protein without lowering mRNA.","evidence":"SBP-tagged pulldown/MS, protein- and RNA-PLA, and ribosome profiling by sucrose gradient sedimentation","pmids":["36008984"],"confidence":"Medium","gaps":["Mechanism by which a membrane protein engages translation machinery unclear","Direct RNA binding versus complex-mediated association not separated"]},{"year":2023,"claim":"Established IFITM1 as a metastasis suppressor in brain colonization through dual immune surveillance: C3-mediated microglial activation and increased MHC-I to enable CD8+ T cell killing.","evidence":"In vivo genome-wide CRISPR screen with co-culture, MHC-I surface, C3 secretion, CD8+ killing, and PD-1 blockade mouse assays","pmids":["36799040"],"confidence":"High","gaps":["How IFITM1 drives C3 secretion mechanistically unknown","Tissue specificity of this protective role versus pro-tumor roles unresolved"]},{"year":2023,"claim":"Reframed IFITM1 as a cholesterol-trafficking factor that a non-enveloped virus hijacks, showing it moves cholesterol from late endosomes to the Golgi and assembles with ACBD3, PI4KB, and OSBP at Aichi virus replication sites.","evidence":"siRNA knockdown, overexpression, Co-IP with ACBD3/PI4KB/OSBP, cholesterol imaging, and pharmacological transport inhibition","pmids":["37252940"],"confidence":"Medium","gaps":["Whether cholesterol transport is the native cellular function or a co-opted one unclear","Direct versus indirect interaction with Golgi proteins not parsed"]},{"year":2023,"claim":"Extended IFITM1's context-dependent roles to cancer invasion and induction pathways, linking it to invasive lung adenocarcinoma via PLK1-FoxM1-STING-TBK1-IRF3 and to suppression of trophoblast invasion.","evidence":"ChIP, kinase assays, and mutagenesis in LUAD; invasion assays, lentiviral transduction, poly(I:C) mouse, and placenta immunostaining for trophoblasts","pmids":["37968723","37434700"],"confidence":"Medium","gaps":["Opposing pro- and anti-invasive effects across tissues not mechanistically reconciled","Direct effectors of invasion control not pinned down"]},{"year":2025,"claim":"Identified the palmitoylation eraser/writer network controlling IFITM1, showing ABHD16A depalmitoylates and inhibits IFITM1 antiviral activity while ABHD17A enhances it indirectly by suppressing ABHD16A.","evidence":"Co-IP, acyl-PEG exchange palmitoylation assays, ABHD16A/ABHD17A perturbation, and CRISPR KO with anti-HBV replication readouts","pmids":["40723864","40434075"],"confidence":"Medium","gaps":["Identity of the palmitoyltransferase writer not established here","Whether ABHD17A acts solely through ABHD16A in all contexts unclear"]},{"year":2025,"claim":"Broadened IFITM1's tissue functions to vascular and epithelial proliferation, implicating c-Src/MAPK/GATA2/E2F2 signaling in atherosclerosis and OVOL1 inhibition in corneal stem cell expansion.","evidence":"RNA-seq, pathway Western blots, proliferation/migration assays, ApoE-/- plaque model, and scRNA-seq with AAV in vivo knockdown","pmids":["40466954","40372397"],"confidence":"Medium","gaps":["Direct molecular targets linking IFITM1 to these pathways not defined","Generalizability across tissues unproven"]},{"year":null,"claim":"It remains unresolved how a single small transmembrane protein integrates such divergent activities—viral entry restriction, cholesterol trafficking, translational control of HLA-B, chromatin/HERV regulation, and tissue-specific proliferation—and whether these reflect distinct topologies, palmitoylation states, or partner complexes.","evidence":"No single study in the timeline reconciles the divergent molecular activities","pmids":[],"confidence":"Low","gaps":["No unified structural model linking topology and palmitoylation to specific functions","Direct biochemical activity (channel, transporter, scaffold) not definitively assigned","Tissue determinants of pro- versus anti-tumor behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[31]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,30]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[29]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[9,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[29]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[31]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,23,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,7,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[19]}],"complexes":["hepatocyte tight junction"],"partners":["CAV1","CD81","OCLN","AP-3","ABHD16A","ABHD17A","SRSF1","HLA-B"],"other_free_text":[]}},"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 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single lab but two orthogonal methods\",\n      \"pmids\": [\"7680491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IFITM1 (9-27 protein) has intrinsic antiviral activity against vesicular stomatitis virus (VSV) but not influenza virus; its intracellular distribution resembles that of cytoskeleton-associated proteins.\",\n      \"method\": \"Constitutive expression of 9-27 cDNA in mouse cells, indirect immunofluorescence, single-cell virus resistance assay\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with functional virus assay and localization imaging, single lab\",\n      \"pmids\": [\"8727077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The rat ortholog of IFITM1 (rat8/9-27 homolog) is required for dome formation in mammary epithelial cells; antisense suppression abolishes dome formation, while forced expression in non-dome-forming cells induces morphological changes suggesting tightened lateral cell connections; the gene is expressed in epithelial tubular structures.\",\n      \"method\": \"Subtractive cDNA library, antisense treatment, forced overexpression, in situ hybridization\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (antisense) and gain-of-function (overexpression) with defined cellular phenotype, single lab\",\n      \"pmids\": [\"9448288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse IFITM1 mediates repulsion of primordial germ cells (PGCs) from the posterior mesoderm into the endoderm via a repulsive mechanism; this activity requires the N-terminal extracellular domain of IFITM1, which cannot be substituted by another IFITM family member's N-terminal domain.\",\n      \"method\": \"Loss-of-function experiments in mouse embryos, domain-swap/chimeric protein analysis, PGC migration tracking\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined PGC phenotype, domain-specificity established by chimeric protein, two orthogonal approaches, replicated in same study\",\n      \"pmids\": [\"16326387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IFITM1 is required downstream of STAT1 for IFN-γ-mediated antiproliferative effects; IFITM1 overexpression inhibits ERK activity, enhances p53 transcriptional activity, and stabilizes p53 by preventing phosphorylation at Thr55; knockdown of IFITM1 blocks IFN-γ antiproliferative activity and confers tumorigenicity to non-malignant hepatocytes.\",\n      \"method\": \"Overexpression and siRNA knockdown of IFITM1, ERK activity assay, p53 transcriptional reporter assay, phosphorylation analysis, nude mouse tumorigenicity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function (siRNA) and gain-of-function (overexpression) with multiple downstream pathway readouts (ERK, p53 phosphorylation, transcription), in vitro and in vivo validation, single lab with multiple orthogonal methods\",\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) through its hydrophobic transmembrane domains; this interaction enhances CAV-1's inhibitory effect on ERK phosphorylation, without IFITM1 directly activating ERK.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, deletion mutagenesis, ERK phosphorylation assay, siRNA knockdown of CAV-1\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mutagenesis plus 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 (but not p38, JNK, or PKC); cross-linking of IFITM1 with a monoclonal antibody induces expression of proinflammatory mediators IL-8 and MMP-9 in THP-1 macrophages.\",\n      \"method\": \"Pathway inhibitors (ERK, PI3K, NF-κB, p38, JNK, PKC), RT-PCR, Western blot, antibody cross-linking of IFITM1\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitors plus direct IFITM1 cross-linking functional assay; multiple inhibitors tested, single lab\",\n      \"pmids\": [\"20847954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Exogenous expression of IFITM1 inhibits HCV replication in immortalized human hepatocytes (IHH) and Huh7 cells, and knockdown enhances HCV replication; IFITM1 overexpression does not block HCV pseudotype entry, suggesting action at a post-entry step.\",\n      \"method\": \"Overexpression and siRNA knockdown in IHH and Huh7 cells, HCV replication assay, HCV pseudotype entry assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional loss- and gain-of-function with both replication and entry assays in two cell lines, single lab\",\n      \"pmids\": [\"21976647\"],\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-immunoprecipitation (IFITM1 with CD81 and occludin), immunofluorescence/confocal microscopy of tight junction localization, patient liver biopsy immunostaining, functional HCV entry assays\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying binding partners, subcellular localization confirmed in cell lines and patient tissue, functional viral entry assay, multiple orthogonal methods\",\n      \"pmids\": [\"22996292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFITM1 restricts virus entry and its intracellular distribution is governed by a C-terminal non-canonical dibasic sorting signal (KRXX); mutating the two basic residues (KR/AA) increases restriction of jaagsiekte sheep retrovirus (JSRV) and amphotropic MLV by altering distribution toward CD63+ multivesicular bodies and away from LAMP1+ lysosomes; IFITM1 binds adaptor protein complex 3 (AP-3), and this association is lost when the dibasic motif is mutated; IFITM1 adopts more than one membrane topology co-existing in cellular membranes.\",\n      \"method\": \"Site-directed mutagenesis of KRXX motif, deconvolution microscopy, co-immunoprecipitation with AP-3, AP-3 knockdown, substituted cysteine accessibility method (SCAM) for topology\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis plus Co-IP plus structural topology assay (SCAM) plus microscopy, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25527505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S-palmitoylation of IFITM1 on conserved and non-conserved cysteines is required for anti-influenza A virus activity; palmitoylation also prevents proteasomal degradation of IFITM1; palmitoylation of the nonconserved C-terminal cysteine supports an intramembrane topology.\",\n      \"method\": \"Palmitoylation assays, site-directed cysteine mutagenesis, proteasome inhibitor treatment, influenza A virus infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific cysteines combined with palmitoylation assay, protein stability assay, and functional antiviral readout; multiple orthogonal methods\",\n      \"pmids\": [\"23804635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S-palmitoylation of all three IFITM proteins (including IFITM1) is essential for anti-HCV activity; the conserved tyrosine residue in the N-terminal domain of IFITM1 is dispensable for anti-HCV activity (in contrast to IFITM2/3 where it regulates localization); IFITM2/3 localize to late and early endosomes and lysosomes in hepatocytes, while IFITM1 co-localizes with CD81.\",\n      \"method\": \"S-palmitoylation assays, site-directed mutagenesis of cysteines and tyrosine residues, HCV entry and replication assays, subcellular co-localization immunofluorescence\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — palmitoylation mutagenesis linked to antiviral function, tyrosine mutant phenotype localization assay, multiple orthogonal methods\",\n      \"pmids\": [\"26354436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFITM-1 does not restrict Rift Valley fever virus (RVFV) infection, while IFITM-2 and IFITM-3 do; IFITM-1 occupies vesicular compartments distinct from those occupied by IFITM-2 and -3.\",\n      \"method\": \"Overexpression of individual IFITMs, viral infection assays with RVFV, vesicle compartment imaging\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with direct viral restriction assay and subcellular compartment imaging; negative result for IFITM1 vs RVFV is mechanistically informative about virus specificity\",\n      \"pmids\": [\"23720721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIV-1 can mutate to evade IFITM1 restriction; mutations in vpu (Vpu34, introducing a premature stop) and env (EnvG367E at the CD4-binding site of gp120) together enable HIV-1 replication in IFITM1-expressing cells by promoting cell-to-cell virus transmission rather than overcoming IFITM1-mediated downregulation of p24 expression.\",\n      \"method\": \"Serial passage of HIV-1 in IFITM1-expressing SupT1 cells, full genome sequencing, mutant virus functional assays, cell-to-cell transmission assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — serial passage selection with genetic identification and functional validation of viral mutations; single lab\",\n      \"pmids\": [\"24725927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IFITM1 does not inhibit infection by HPV16, human cytomegalovirus (HCMV), or adenovirus type 5; IFITM1 and IFITM3 modestly enhanced HPV16 infection in multiple cell types including primary keratinocytes.\",\n      \"method\": \"Overexpression in multiple cell types including primary keratinocytes, viral infection assays for HPV16, HCMV, and Ad5\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression functional assay across multiple cell types and three DNA viruses; finding is a negative result for restriction but a positive finding for modest HPV enhancement\",\n      \"pmids\": [\"24827144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The C-terminal 9 amino acids of IFITM1 contain a sorting signal that suppresses anti-HIV-1 activity; deletion of residues 117–125 (Δ117-125) relocates IFITM1 predominantly to the plasma membrane where HIV-1 entry occurs and enables 3-fold inhibition of HIV-1 entry; wild-type human IFITM1 (which has a longer C-terminus compared to mouse IFITM1) does not inhibit HIV-1 entry.\",\n      \"method\": \"C-terminal deletion mutagenesis, subcellular localization imaging, HIV-1 entry assay, comparison of human vs. mouse IFITM1\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with localization imaging and functional entry assay; single lab\",\n      \"pmids\": [\"25738301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFITM1 loss of function in AI-resistant MCF-7:5C cells markedly increases p21 transcription, expression, and nuclear localization mediated by JAK/STAT activation; IFITM1 overexpression in wild-type MCF-7 cells promotes estrogen-independent growth.\",\n      \"method\": \"Lentivirus shRNA knockdown, overexpression, orthotopic and MIND mouse models, p21 reporter assays, JAK/STAT inhibition\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional loss/gain-of-function with in vivo model and mechanistic p21/JAK-STAT pathway assays; single lab\",\n      \"pmids\": [\"28411130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IFITM1 promotes CRC cell migration/invasion through a mechanism involving CAV-1 as a downstream target; knockdown of CAV-1 abrogates IFITM1-siRNA-mediated inhibition of cell invasion, placing CAV-1 downstream of IFITM1 in a pro-invasive pathway.\",\n      \"method\": \"Overexpression and siRNA knockdown of IFITM1, siRNA knockdown of CAV-1, migration/invasion assays, epistasis rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (rescue assay) placing CAV-1 downstream of IFITM1, single lab\",\n      \"pmids\": [\"27852071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IFITM1 overexpression in SUM149 IBC cells promotes aggressiveness in a STAT2-dependent manner; STAT2 knockdown abolishes IFITM1 expression and IFITM1 promoter activity; STAT2-mediated IFITM1 activation is dependent on the chromatin remodeler BRG1.\",\n      \"method\": \"siRNA/shRNA knockdown of IFITM1, STAT1/2, and BRG1; luciferase promoter assays; migration, invasion, and colony formation assays\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase promoter assay plus knockdown of upstream regulators plus functional phenotypic readouts; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26897526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An IFN-responsive enhancer located 35 kb upstream of IFITM3 coordinately upregulates IFN-induced expression of IFITM1, IFITM2, and IFITM3 genes; STAT1 binds this enhancer upon IFN treatment; chromatin looping brings the IFITM gene cluster into physical contact with this distal enhancer; in vivo truncation of the enhancer impairs IFN-induced resistance to influenza A virus.\",\n      \"method\": \"Luciferase reporter assay, CRISPR-Cas9 genome editing (in vivo enhancer truncation), ChIP assay, EMSA, 3C (chromosome conformation capture)\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, EMSA, 3C, CRISPR in vivo deletion) with functional antiviral readout; rigorous study\",\n      \"pmids\": [\"28511927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HPV infection downregulates IFITM1 expression; knockdown of IFITM1 in uninfected keratinocytes confirms its role in IFN-γ/TNF-α-mediated antiproliferative effects and in regulating RARRES1 expression.\",\n      \"method\": \"siRNA knockdown of IFITM1, cell growth/proliferation assays, gene expression analysis, S-phase arrest analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with downstream gene and proliferation readout, single lab\",\n      \"pmids\": [\"27920775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IFITM1 suppresses expression of human endogenous retroviruses (HERVs) in human embryonic stem cells (hESCs) by regulating epigenetic modifications; IFITM1 knockout (CRISPR/Cas9) increases HERV expression and reduces trimethylation of H3K9 at HERV loci.\",\n      \"method\": \"CRISPR/Cas9 knockout of IFITM1 in hESCs, HERV expression analysis, H3K9me3 ChIP at HERV loci\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with epigenetic readout at specific loci, single lab\",\n      \"pmids\": [\"28781951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"G3BP1 and G3BP2 RNA-binding proteins are essential for the accumulation of IFITM1 protein and regulate IFITM1 expression through both the MEK pathway and interaction with the 3'-UTR of IFITM1 transcripts.\",\n      \"method\": \"G3BP knockdown, MEK pathway inhibition, 3'-UTR interaction assays, Western blot of IFITM protein levels\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, G3BP knockdown with protein level readout, 3'-UTR interaction assay not fully characterized by method in abstract\",\n      \"pmids\": [\"31172368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFITM1 and IFITM3 double knockout in cervical cancer cells attenuates IFNγ-stimulated synthesis of IRF1, HLA-B, and ISG15; SBP-tagged IFITM1 co-associates with ISG15 and HLA-B by SWATH-IP mass spectrometry; HLA-B interacts with IFITM1/3 by proximity ligation assay; ISG15ylation is attenuated in IFITM1/IFITM3 double-null cells; IFITM1-targeted siRNA attenuates an IFN-regulated protein subpopulation including MHC Class I molecules.\",\n      \"method\": \"CRISPR-Cas9 double KO, pulse SILAC, SWATH-IP mass spectrometry, proximity ligation assay, siRNA knockdown\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (CRISPR KO, SILAC, MS, PLA), single lab\",\n      \"pmids\": [\"30951861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MUC1 interacts with STAT1 via JAK/STAT signaling to drive IFITM1 transcription; knockdown of MUC1 by siRNA or pharmacological inhibitors abrogates IFITM1 mRNA and protein expression; in vivo, estrogen and ruxolitinib reduce MUC1, P-STAT1, and IFITM1 expression.\",\n      \"method\": \"siRNA knockdown of MUC1, pharmacological inhibitors, Western blot, in vivo mouse model with ruxolitinib treatment\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA and inhibitor) with defined downstream IFITM1 expression readout, in vivo validation, single lab\",\n      \"pmids\": [\"30655323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBV core protein (HBc) inhibits IFNα-induced IFITM1 expression by interacting with BAF200 (a component of the PBAF chromatin remodeling complex); basal IFITM1 expression depends on BAF200, not the JAK-STAT1 pathway; HBc-BAF200 interaction disrupts PBAF complex stability and suppresses IFITM1 transcription.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation (HBc-BAF200 interaction), Western blot, HBV replication assay, co-transfection rescue experiments\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, mechanistic rescue experiment, multiple cell lines; single lab\",\n      \"pmids\": [\"31075894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NF-κB and IRF1 transcription factors bind an enhancer region (R2, 2 kb upstream) of the IFITM1 gene to mediate LPS-stimulated IFITM1 expression and hMSC migration; LPS treatment increases enhancer RNA expression at R2 and H3K27ac enrichment at R2; knockdown of IFITM1 impairs LPS-stimulated cell migration.\",\n      \"method\": \"ChIP sequencing, ChIP-PCR, luciferase reporter assay, qRT-PCR for enhancer RNAs, RNAi (NF-κB and IRF1), wound healing assay\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (ChIP-seq, luciferase, RNAi), single lab\",\n      \"pmids\": [\"31910882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFITM1 expression determined by APC/Wnt signaling controls extracellular vesicle (EV) uptake in colorectal cancer; APC mutation induces IFITM1 expression; IFITM1high CRC cells show markedly reduced uptake of fibroblast EVs; inactivation of IFITM1 enhances EV uptake.\",\n      \"method\": \"Mouse and patient-derived organoids, APC mutation models, IFITM1 knockout/knockdown, EV uptake assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (IFITM1 inactivation) with functional EV uptake assay in organoid models, single lab\",\n      \"pmids\": [\"34609520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NF-κB is an important downstream target of IFITM1 in TNBC; siRNA/CRISPR KO of IFITM1 inhibits proliferation, colony formation, and wound healing in vitro and reduces tumor growth/invasion in vivo; RNA-seq of IFITM1 KO cells reveals downregulation of genes involved in proliferation, migration, and invasion.\",\n      \"method\": \"siRNA and CRISPR/Cas9 knockout, RNA-seq, orthotopic and MIND mouse models, NF-κB siRNA rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with RNA-seq pathway analysis and in vivo validation, single lab\",\n      \"pmids\": [\"34022283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFITM1 associates with the splicing factor SRSF1 (predominantly in the cytosol); IFITM1/3 interact with HLA-B mRNA in response to IFNγ; IFITM1/3 double KO cells show a reduction in the 80S ribosomal fraction; loss of IFITM1/3 reduces HLA-B protein synthesis without affecting HLA-B mRNA levels, placing IFITM1 function at the translational rather than transcriptional level for HLA-B.\",\n      \"method\": \"SBP-tagged IFITM1 pulldown/MS, proximity ligation assay (protein-protein and RNA-protein), ribosome profiling by sucrose gradient sedimentation, RT-qPCR, RNA-seq\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (PLA, ribosome profiling, RNA-protein interaction), single lab\",\n      \"pmids\": [\"36008984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM1 high expression in incipient brain metastatic lung cancer cells mediates immune surveillance by: secreting complement component C3 to activate microglia and by increasing MHC class I surface expression to enhance CD8+ T cell cytolytic activity; loss of IFITM1 promotes brain colonization by escaping both innate (microglia phagocytosis) and adaptive (CD8+ T cell killing) immune responses.\",\n      \"method\": \"In vivo genome-wide CRISPR-Cas9 screen, IFITM1 overexpression/knockdown, co-culture assays, MHC-I surface expression assays, C3 secretion measurement, CD8+ T cell killing assay, PD-1 blockade mouse model\",\n      \"journal\": \"EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen validated by multiple functional assays (immune cell killing, phagocytosis, MHC-I surface expression, C3 secretion) in vitro and in vivo; single lab but rigorous with multiple orthogonal readouts\",\n      \"pmids\": [\"36799040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM1 facilitates cholesterol transport from late endosomes to the Golgi, which is exploited by Aichi virus (a non-enveloped RNA virus) to form cholesterol-rich replication sites; IFITM1 localizes to viral RNA replication sites; IFITM1 interacts with viral proteins and host Golgi proteins ACBD3, PI4KB, and OSBP at replication sites; IFITM1 knockdown significantly reduces AiV RNA replication.\",\n      \"method\": \"siRNA knockdown, overexpression, co-immunoprecipitation (IFITM1 with ACBD3, PI4KB, OSBP), fluorescence imaging of cholesterol distribution, pharmacological inhibition of ER-Golgi cholesterol transport\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional knockdown plus cholesterol imaging; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37252940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFN-β-induced IFITM1 upregulation impairs extravillous cytotrophoblast (EVCT) invasion; transduction of IFITM1 into trophoblast cells directly reduces invasive ability; IFITM1 is upregulated in CMV- and bacterially infected human placentas.\",\n      \"method\": \"In vitro/ex vivo EVCT invasion assays, IFITM1 transduction (lentiviral), in vivo poly(I:C) mouse model, human pathological placenta immunostaining\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function (transduction) with defined cellular invasion phenotype, confirmed in vivo mouse model and human tissue; single lab\",\n      \"pmids\": [\"37434700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFITM1 is upregulated in invasive lung adenocarcinoma (LUAD) with phosphomimetic FoxM1 (phosphorylated at Ser25 by PLK1) through activation of the STING-TBK1-IRF3 signaling pathway.\",\n      \"method\": \"Immunoprecipitation, kinase assay, site-directed mutagenesis, chromatin immunoprecipitation, microarray analysis, LC-MS/MS\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, kinase assay, and mutagenesis linking PLK1-FoxM1-STING pathway to IFITM1 induction; single lab, multiple methods\",\n      \"pmids\": [\"37968723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17A physically interacts with IFITM1 and paradoxically increases its S-palmitoylation level (and thereby antiviral activity) not by directly palmitoylating it, but by downregulating the depalmitoylase ABHD16A; ABHD16A catalyzes depalmitoylation of IFITM1 and negatively regulates its antiviral activity, and ABHD17A counteracts this by suppressing ABHD16A.\",\n      \"method\": \"Co-immunoprecipitation, acyl-PEG exchange gel-shift palmitoylation assay, ABHD16A knockdown/overexpression, antiviral activity assays\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with palmitoylation assay and functional antiviral readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40723864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD16A catalyzes depalmitoylation of IFITM1 in HepG2.215 cells and negatively regulates its anti-HBV activity; CRISPR/Cas9 knockout of ABHD16A enhances IFITM1-mediated restriction of HBV replication; the anti-HBV activity of IFITM1 depends on palmitoylation modification.\",\n      \"method\": \"Co-immunoprecipitation, acyl-PEGyl exchange gel-shift assay (APEGS), CRISPR/Cas9 knockout of IFITM1 and ABHD16A, HBV replication assay\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — palmitoylation assay plus CRISPR KO with functional viral replication readout, single lab\",\n      \"pmids\": [\"40434075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFITM1 promotes VSMC proliferation, migration, and macrophage-like transdifferentiation via the c-Src/MAPK/GATA2/E2F2 signaling pathway; overexpression of IFITM1 upregulates p-Src, p-p38 MAPK, p-GATA2, and E2F2 levels; in vivo overexpression accelerates atherosclerotic plaque formation in ApoE-/- mice.\",\n      \"method\": \"RNA sequencing, Western blot (pathway intermediates), cell viability/flow cytometry/wound healing/transwell assays, ApoE-/- mouse model, IFITM1 overexpression\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pathway intermediate measurements and in vivo plaque model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40466954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFITM1 promotes limbal epithelial stem/early transient amplifying (eTA) cell expansion after corneal wounding partly through inhibition of OVOL1, a negative regulator of epithelial cell proliferation; in vivo AAV-mediated knockdown of IFITM1 significantly attenuates stem/eTA cell expansion and activation after corneal injury.\",\n      \"method\": \"Single-cell RNA sequencing, AAV-mediated in vivo IFITM1 knockdown, human limbal epithelial cell proliferation assays, OVOL1 pathway analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV KD plus in vitro proliferation assay with pathway (OVOL1) analysis; single lab\",\n      \"pmids\": [\"40372397\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFITM1 is an interferon-induced transmembrane protein that restricts entry of diverse enveloped RNA viruses (acting at endosomal/tight-junction stages) and some non-enveloped viruses (by facilitating cholesterol trafficking to replication sites), with its antiviral and cellular functions critically dependent on S-palmitoylation of conserved cysteines (regulated by writers such as DHHC enzymes and erasers ABHD16A/ABHD17A), while in non-viral contexts it mediates IFN-γ antiproliferative signaling downstream of STAT1 by inhibiting ERK through CAV-1 interaction and stabilizing p53, governs primordial germ cell repulsion via its N-terminal extracellular domain, promotes or suppresses tumor cell invasion depending on cancer context (often through CAV-1 and NF-κB downstream), facilitates MHC class I surface expression and immune surveillance of metastatic cells, and is transcriptionally regulated by STAT1/STAT2 binding to a distal IFN-responsive enhancer via long-range chromatin looping.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFITM1 is an interferon-induced transmembrane protein that restricts entry and replication of diverse viruses while also serving as a signaling and developmental effector in non-viral contexts [#1, #4, #8]. As an antiviral restriction factor, IFITM1 blocks vesicular stomatitis virus and acts at post-entry or entry steps against HCV, where it localizes to hepatocyte tight junctions and physically interacts with the HCV co-receptors CD81 and occludin to disrupt viral entry [#1, #7, #8]. Its antiviral activity and protein stability depend critically on S-palmitoylation of conserved cysteines, which is countered by the depalmitoylase ABHD16A and indirectly enhanced by ABHD17A through suppression of ABHD16A [#10, #34, #35]. IFITM1 intracellular distribution and membrane topology are governed by a C-terminal non-canonical dibasic (KRXX) sorting signal that binds adaptor protein complex AP-3, directing the protein among endosomal compartments and the plasma membrane and thereby tuning which viruses it restricts [#9, #15]. Distinct from restriction, IFITM1 can facilitate cholesterol transport from late endosomes to the Golgi, a function exploited by the non-enveloped Aichi virus to build cholesterol-rich replication sites, where IFITM1 associates with ACBD3, PI4KB, and OSBP [#31]. In non-viral signaling, IFITM1 functions downstream of STAT1 to mediate IFN-\\u03b3 antiproliferative effects by inhibiting ERK\\u2014partly through interaction with caveolin-1 at caveolae\\u2014and by stabilizing p53 [#4, #5]. IFITM1 also supports IFN-\\u03b3-driven MHC class I expression and immune surveillance of metastatic cells, acting at the translational level to promote HLA-B synthesis and secreting complement C3 to recruit microglia [#23, #29, #30]. In development, IFITM1 mediates repulsion of primordial germ cells via its N-terminal extracellular domain [#3]. Its transcription is controlled by STAT1/STAT2 binding to a distal IFN-responsive enhancer engaged through long-range chromatin looping [#19]. Across cancers IFITM1 has context-dependent pro- or anti-tumor roles, frequently signaling through CAV-1 and NF-\\u03baB [#17, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the first functional activity for the interferon-inducible 9-27 protein, framing IFITM1 as an antiviral effector capable of binding RNA and interfering with viral gene expression.\",\n      \"evidence\": \"cDNA library screen for RRE-binding proteins, in vitro RNA-binding assay, and HIV-1 expression assay after transfection in human cells\",\n      \"pmids\": [\"7680491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA binding shown in vitro only, with unclear physiological relevance\", \"Did not establish whether antiviral effect was direct or via host signaling\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated that IFITM1 has intrinsic, virus-selective antiviral activity (active against VSV, inactive against influenza), establishing virus specificity as a defining feature.\",\n      \"evidence\": \"Constitutive expression of 9-27 cDNA in mouse cells with single-cell virus resistance assay and immunofluorescence localization\",\n      \"pmids\": [\"8727077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of virus selectivity not defined\", \"Subcellular localization only described qualitatively\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linked IFITM1 to epithelial cell-cell junction biology by showing its ortholog is required for dome formation in mammary epithelia, revealing a non-antiviral cellular role.\",\n      \"evidence\": \"Subtractive cDNA library, antisense suppression, forced overexpression, and in situ hybridization in rat mammary epithelial cells\",\n      \"pmids\": [\"9448288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners at junctions not identified\", \"Used the rat ortholog rather than human IFITM1\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined a developmental function in primordial germ cell repulsion and mapped it to the N-terminal extracellular domain, demonstrating domain-specific, non-antiviral signaling.\",\n      \"evidence\": \"Loss-of-function in mouse embryos plus domain-swap chimera analysis and PGC migration tracking\",\n      \"pmids\": [\"16326387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/ligand mediating repulsion not identified\", \"Downstream signaling unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed IFITM1 downstream of STAT1 as a required mediator of IFN-\\u03b3 antiproliferative signaling, connecting it to ERK inhibition and p53 stabilization and to tumor suppression.\",\n      \"evidence\": \"Overexpression and siRNA knockdown with ERK and p53 reporter/phosphorylation assays and nude mouse tumorigenicity assay\",\n      \"pmids\": [\"16847454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target by which IFITM1 inhibits ERK not defined here\", \"Mechanism of p53 Thr55 phosphorylation prevention unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified caveolin-1 as a physical partner, providing a molecular route by which IFITM1 enhances ERK inhibition without itself being a kinase.\",\n      \"evidence\": \"Immunofluorescence, co-immunoprecipitation, deletion mutagenesis, ERK phosphorylation assay, and CAV-1 knockdown\",\n      \"pmids\": [\"19499152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction without reciprocal validation in multiple systems\", \"How transmembrane-domain binding modulates CAV-1 activity not structurally defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed IFITM1 is induced via CD147/cyclophilin A through ERK, PI3K, and NF-\\u03baB and can itself drive proinflammatory output, implicating it in inflammatory signaling.\",\n      \"evidence\": \"Pathway inhibitors, RT-PCR, Western blot, and antibody cross-linking of IFITM1 in THP-1 macrophages\",\n      \"pmids\": [\"20847954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-linking is a surrogate for natural ligation\", \"Direct downstream effectors of IFITM1 signaling not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established IFITM1 as an anti-HCV factor acting post-entry, distinguishing its mechanism from a pure entry block.\",\n      \"evidence\": \"Bidirectional overexpression and knockdown in IHH and Huh7 cells with HCV replication and pseudotype entry assays\",\n      \"pmids\": [\"21976647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Post-entry step not molecularly defined\", \"Apparent tension with later entry-block findings unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Localized IFITM1 to hepatocyte tight junctions and identified CD81 and occludin as binding partners, defining an entry-disruption mechanism against HCV relevant in patient tissue.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal localization in cells and patient liver biopsies, and functional HCV entry assays\",\n      \"pmids\": [\"22996292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFITM1 blocks entry by occluding co-receptors or altering membrane properties not resolved\", \"Reconciliation with the earlier post-entry result not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the trafficking and topology determinants of IFITM1: a C-terminal dibasic KRXX motif that binds AP-3 and controls endosomal distribution and restriction breadth, with the protein adopting multiple membrane topologies.\",\n      \"evidence\": \"Site-directed mutagenesis, deconvolution microscopy, AP-3 Co-IP and knockdown, and SCAM topology mapping\",\n      \"pmids\": [\"25527505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of multiple co-existing topologies unknown\", \"How distribution shifts translate into altered restriction mechanistically unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified S-palmitoylation of conserved cysteines as essential for IFITM1 antiviral activity and protein stability, establishing a post-translational switch controlling function.\",\n      \"evidence\": \"Palmitoylation assays, cysteine mutagenesis, proteasome inhibition, and influenza A and HCV infection assays\",\n      \"pmids\": [\"23804635\", \"26354436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferases acting on IFITM1 not identified in these studies\", \"Why the N-terminal tyrosine is dispensable for IFITM1 but not IFITM2/3 not mechanistically explained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped IFITM1's antiviral specificity by negative results, showing it fails to restrict RVFV, HPV16, HCMV, and Ad5 and even modestly enhances HPV16, refining which viruses it acts upon and where its compartments differ from IFITM2/3.\",\n      \"evidence\": \"Overexpression of individual IFITMs with viral restriction assays and vesicle compartment imaging across multiple cell types\",\n      \"pmids\": [\"23720721\", \"24827144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of HPV16 enhancement not defined\", \"Compartment differences described but not functionally tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated viral evolutionary escape from IFITM1 via vpu and env mutations promoting cell-to-cell spread, illuminating how restriction is countered.\",\n      \"evidence\": \"Serial passage of HIV-1 in IFITM1-expressing SupT1 cells with genome sequencing and cell-to-cell transmission assays\",\n      \"pmids\": [\"24725927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular interaction between IFITM1 and viral proteins not shown\", \"Generalizability beyond passaged strains uncertain\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that the C-terminal sorting signal restrains IFITM1 anti-HIV activity by keeping it off the plasma membrane, explaining why human IFITM1 normally fails to block HIV entry.\",\n      \"evidence\": \"C-terminal deletion mutagenesis, subcellular localization imaging, HIV-1 entry assays, and human vs. mouse comparison\",\n      \"pmids\": [\"25738301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect modest (3-fold) and confined to a deletion mutant\", \"Physiological relevance of relocated IFITM1 unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved how IFN coordinately induces the IFITM cluster, showing STAT1 binds a distal enhancer that loops to the IFITM genes and is required for antiviral resistance in vivo.\",\n      \"evidence\": \"Luciferase reporter, ChIP, EMSA, 3C chromosome conformation capture, and CRISPR in vivo enhancer truncation\",\n      \"pmids\": [\"28511927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each IFITM gene to the in vivo phenotype not separated\", \"Looping architecture not resolved at base-pair detail\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed epigenetic and developmental functions, showing IFITM1 silences HERVs via H3K9me3 and contributes to IFN-\\u03b3/TNF-\\u03b1 antiproliferative control of keratinocytes, broadening its non-viral repertoire.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in hESCs with HERV expression and H3K9me3 ChIP; siRNA knockdown with proliferation and RARRES1 readouts in keratinocytes\",\n      \"pmids\": [\"28781951\", \"27920775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a transmembrane protein influences chromatin marks at HERV loci is mechanistically unexplained\", \"Direct versus indirect epigenetic effects not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Diversified IFITM1's expression control, identifying MUC1-STAT1, NF-\\u03baB/IRF1 enhancer engagement, BAF200/PBAF for basal expression, and G3BP-dependent protein accumulation as distinct regulatory inputs.\",\n      \"evidence\": \"siRNA/inhibitor studies, ChIP-seq and luciferase enhancer assays, yeast two-hybrid and Co-IP, and 3'-UTR interaction assays across cell models\",\n      \"pmids\": [\"30655323\", \"31910882\", \"31075894\", \"31172368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G3BP regulation rests on incompletely characterized methods (Low confidence)\", \"Hierarchy among these regulatory inputs in a single cell type unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected IFITM1 to MHC class I immune surveillance, showing IFITM1/3 are needed for IFN-\\u03b3-stimulated HLA-B and ISG15 synthesis and associate with ISG15 and HLA-B.\",\n      \"evidence\": \"CRISPR double KO, pulse SILAC, SWATH-IP mass spectrometry, proximity ligation, and siRNA in cervical cancer cells\",\n      \"pmids\": [\"30951861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether interactions are direct not established by PLA alone\", \"Step in HLA-B production affected not yet defined here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localized IFITM1's role in HLA-B production to translation, showing it interacts with SRSF1 and HLA-B mRNA and that its loss reduces HLA-B protein without lowering mRNA.\",\n      \"evidence\": \"SBP-tagged pulldown/MS, protein- and RNA-PLA, and ribosome profiling by sucrose gradient sedimentation\",\n      \"pmids\": [\"36008984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which a membrane protein engages translation machinery unclear\", \"Direct RNA binding versus complex-mediated association not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established IFITM1 as a metastasis suppressor in brain colonization through dual immune surveillance: C3-mediated microglial activation and increased MHC-I to enable CD8+ T cell killing.\",\n      \"evidence\": \"In vivo genome-wide CRISPR screen with co-culture, MHC-I surface, C3 secretion, CD8+ killing, and PD-1 blockade mouse assays\",\n      \"pmids\": [\"36799040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IFITM1 drives C3 secretion mechanistically unknown\", \"Tissue specificity of this protective role versus pro-tumor roles unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reframed IFITM1 as a cholesterol-trafficking factor that a non-enveloped virus hijacks, showing it moves cholesterol from late endosomes to the Golgi and assembles with ACBD3, PI4KB, and OSBP at Aichi virus replication sites.\",\n      \"evidence\": \"siRNA knockdown, overexpression, Co-IP with ACBD3/PI4KB/OSBP, cholesterol imaging, and pharmacological transport inhibition\",\n      \"pmids\": [\"37252940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cholesterol transport is the native cellular function or a co-opted one unclear\", \"Direct versus indirect interaction with Golgi proteins not parsed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended IFITM1's context-dependent roles to cancer invasion and induction pathways, linking it to invasive lung adenocarcinoma via PLK1-FoxM1-STING-TBK1-IRF3 and to suppression of trophoblast invasion.\",\n      \"evidence\": \"ChIP, kinase assays, and mutagenesis in LUAD; invasion assays, lentiviral transduction, poly(I:C) mouse, and placenta immunostaining for trophoblasts\",\n      \"pmids\": [\"37968723\", \"37434700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing pro- and anti-invasive effects across tissues not mechanistically reconciled\", \"Direct effectors of invasion control not pinned down\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the palmitoylation eraser/writer network controlling IFITM1, showing ABHD16A depalmitoylates and inhibits IFITM1 antiviral activity while ABHD17A enhances it indirectly by suppressing ABHD16A.\",\n      \"evidence\": \"Co-IP, acyl-PEG exchange palmitoylation assays, ABHD16A/ABHD17A perturbation, and CRISPR KO with anti-HBV replication readouts\",\n      \"pmids\": [\"40723864\", \"40434075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the palmitoyltransferase writer not established here\", \"Whether ABHD17A acts solely through ABHD16A in all contexts unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened IFITM1's tissue functions to vascular and epithelial proliferation, implicating c-Src/MAPK/GATA2/E2F2 signaling in atherosclerosis and OVOL1 inhibition in corneal stem cell expansion.\",\n      \"evidence\": \"RNA-seq, pathway Western blots, proliferation/migration assays, ApoE-/- plaque model, and scRNA-seq with AAV in vivo knockdown\",\n      \"pmids\": [\"40466954\", \"40372397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets linking IFITM1 to these pathways not defined\", \"Generalizability across tissues unproven\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single small transmembrane protein integrates such divergent activities\\u2014viral entry restriction, cholesterol trafficking, translational control of HLA-B, chromatin/HERV regulation, and tissue-specific proliferation\\u2014and whether these reflect distinct topologies, palmitoylation states, or partner complexes.\",\n      \"evidence\": \"No single study in the timeline reconciles the divergent molecular activities\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model linking topology and palmitoylation to specific functions\", \"Direct biochemical activity (channel, transporter, scaffold) not definitively assigned\", \"Tissue determinants of pro- versus anti-tumor behavior unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 30]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [9, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 23, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 7, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\"hepatocyte tight junction\"],\n    \"partners\": [\"CAV1\", \"CD81\", \"OCLN\", \"AP-3\", \"ABHD16A\", \"ABHD17A\", \"SRSF1\", \"HLA-B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":10,"faith_total":10,"faith_pct":100.0}}