Affinage

IFITM3

Interferon-induced transmembrane protein 3 · UniProt Q01628

Length
133 aa
Mass
14.6 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFITM3 is an interferon-induced intramembrane protein that restricts entry of diverse enveloped viruses by altering endosomal membrane properties, and additionally modulates γ-secretase activity, PI3K signaling, and phagosome maturation in cell-type-specific contexts. IFITM3 localizes to endolysosomes via a YxxΦ/AP-2-dependent endocytic sorting motif and, once there, oligomerizes through a GxxxG motif, binds cholesterol via its amphipathic helix, and induces local lipid sorting that stabilizes hemifusion intermediates and blocks fusion pore formation, thereby trapping viral particles for lysosomal degradation (PMID:33112230, PMID:37003257, PMID:35872070, PMID:24521078). Its antiviral activity is positively regulated by S-palmitoylation (mediated redundantly by ZDHHC20, ZDHHC3, ZDHHC7) and LSD1-dependent K88 demethylation, and negatively regulated by NEDD4-mediated ubiquitination that targets it for lysosomal turnover via VCP/p97-dependent sorting (PMID:20601941, PMID:29079573, PMID:29281729, PMID:26263374, PMID:32243810). Beyond antiviral defense, IFITM3 binds and activates γ-secretase to increase amyloid-β production in neurons, astrocytes, and cerebrovascular endothelial cells, and in B cells phosphorylation at Tyr20 redirects IFITM3 to the plasma membrane where it scaffolds PIP3 to amplify PI3K signaling (PMID:32879487, PMID:39807629, PMID:33149299).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2010 High

    Establishing that IFITM3 blocks an early post-endocytic entry step and that S-palmitoylation is a key post-translational switch for its antiviral activity answered the fundamental question of how this IFN-induced protein restricts virus infection.

    Evidence Chemical reporter palmitoylome profiling, cysteine mutagenesis, VSV/influenza infection assays in cell lines

    PMID:20601941 PMID:20943977

    Open questions at the time
    • Identity of palmitoyl-acyltransferase(s) unknown at this time
    • Mechanism of membrane-level restriction unresolved
    • In vivo relevance not yet tested
  2. 2012 High

    Demonstrating that IFITM3 is essential for surviving influenza infection in vivo and that it localizes to endolysosomes via its N-terminal sorting region established IFITM3 as a non-redundant innate immune effector whose subcellular targeting is critical for function.

    Evidence Ifitm3 knockout mice challenged with influenza, topology mapping by glycosylation insertion, deletion mutagenesis, subcellular imaging

    PMID:22446628 PMID:22511783 PMID:23055554

    Open questions at the time
    • Sorting motif not yet mapped to a specific endocytic adaptor
    • Membrane topology model debated
    • Mechanism of fusion blockade at the membrane biophysics level unknown
  3. 2013 High

    Identification of the VAPA interaction and cholesterol accumulation in endosomes provided the first mechanistic link between IFITM3 and membrane lipid remodeling as a basis for fusion inhibition.

    Evidence Co-immunoprecipitation of IFITM3–VAPA, cholesterol localization assays, viral entry assays in VAPA-depleted cells

    PMID:23601107

    Open questions at the time
    • Whether VAPA interaction is necessary versus sufficient for restriction unclear
    • Direct cholesterol binding by IFITM3 not yet shown
    • Contribution of other lipid species not tested
  4. 2014 High

    Mapping the YxxΦ motif and its interaction with AP-2/μ2 resolved how IFITM3 reaches endosomes via clathrin-mediated endocytosis and why endosomal targeting is required for restricting pH-dependent viruses.

    Evidence YxxΦ motif mutagenesis, μ2 depletion/overexpression, localization imaging, influenza and VSV infection assays

    PMID:24521078

    Open questions at the time
    • Whether AP-2-independent pathways also contribute to IFITM3 trafficking not addressed
    • Role of phosphorylation at Y20 in modulating this sorting not yet recognized
  5. 2015 High

    Identification of NEDD4 as the E3 ligase that ubiquitinates IFITM3 via a PPxY motif and targets it for lysosomal degradation established ubiquitination as a negative regulatory axis controlling IFITM3 protein levels and antiviral potency.

    Evidence In vitro ubiquitination reconstitution, NEDD4 KO MEFs, PPxY mutagenesis, lysosome inhibitor treatment, influenza infection assays

    PMID:26263374

    Open questions at the time
    • Which specific lysine sites are ubiquitinated incompletely mapped
    • Role of deubiquitinases not explored
    • Interplay between ubiquitination and palmitoylation not resolved
  6. 2016 High

    EPR and NMR structural studies resolved the intramembrane topology of IFITM3 — a single C-terminal transmembrane helix with an N-terminal intramembrane segment — and linked this topology to enhanced hemifusion, providing a biophysical framework for the antiviral mechanism.

    Evidence Site-directed spin labeling, EPR spectroscopy, solution NMR in detergent micelles

    PMID:27046158

    Open questions at the time
    • Structure determined in detergent micelles, not in native membranes
    • How topology relates to oligomerization not addressed
    • No high-resolution structure in lipid bilayer
  7. 2017 High

    Systematic screening identified ZDHHC20 as the primary lysosome-localized palmitoyltransferase for IFITM3 and revealed functional redundancy among multiple ZDHHCs, while discovery that LSD1 demethylates K88 to activate IFITM3 established a second post-translational regulatory layer.

    Evidence ZDHHC KO/overexpression screen, palmitoylation assays, LSD1 in vitro demethylation, LSD1 inhibitor in mouse IAV model, co-IP

    PMID:29079573 PMID:29281729

    Open questions at the time
    • Relative contributions of individual ZDHHCs in physiological contexts unclear
    • K88 methyltransferase not identified
    • How methylation and palmitoylation are coordinated unknown
  8. 2019 High

    Live-cell imaging with site-specific labeling demonstrated that IFITM3 is present on endocytic vesicles that actively fuse with incoming virions and routes restricted viral cargo to lysosomes, shifting the model from passive membrane alteration to active co-trafficking.

    Evidence CRISPR IFITM-mutant cell lines, site-specific fluorophore tagging, live-cell imaging of viral entry

    PMID:30643282

    Open questions at the time
    • How IFITM3-bearing vesicles are selectively targeted to virus-containing endosomes unknown
    • Whether co-trafficking requires specific lipid or protein cofactors not determined
  9. 2020 High

    A series of landmark studies expanded IFITM3 biology beyond antiviral defense: IFITM3 was shown to bind and activate γ-secretase (increasing Aβ production relevant to Alzheimer's disease), to function as a PIP3 scaffold amplifying PI3K signaling in B cells upon Tyr20 phosphorylation, and to require VCP/p97 for ubiquitin-dependent trafficking and turnover.

    Evidence γ-secretase Co-IP and activity assays in 5xFAD mice and human AD tissue; phosphomimetic mutants and Ifitm3−/− B cells with BCR signaling readouts; photo-crosslinking proteomics identifying VCP, K24 mutagenesis, VCP inhibitor treatment

    PMID:32243810 PMID:32879487 PMID:33149299

    Open questions at the time
    • Structural basis of IFITM3–γ-secretase interaction unknown
    • How Tyr20 phosphorylation overrides AP-2 sorting mechanistically unclear
    • Whether VCP acts on IFITM3 as an unfoldase or segregase not determined
  10. 2020 High

    Demonstration that GxxxG-mediated oligomerization drives membrane rigidity and that IFITM3 incorporation into virions reduces HA content revealed two distinct mechanistic arms — endosomal membrane stiffening and virion-intrinsic attenuation.

    Evidence G95 mutagenesis with oligomerization and membrane rigidity assays; virion IFITM3/HA quantification, neutralization assays, mouse infection model

    PMID:33112230 PMID:33882122

    Open questions at the time
    • Stoichiometry of functional oligomers not defined
    • Relative contribution of virion incorporation versus endosomal restriction in vivo not quantified
  11. 2021 High

    IFITM3 was found to suppress phagosome maturation in macrophages, revealing a host-detrimental role where IFN-induced IFITM3 paradoxically facilitates intracellular bacterial infection by preventing lysosomal killing of Listeria.

    Evidence Ifitm3−/− mouse Listeria infection model, phagosome maturation and virulence factor proteolysis assays

    PMID:34404769

    Open questions at the time
    • Molecular mechanism by which IFITM3 inhibits phagosome maturation not defined
    • Whether other intracellular bacteria exploit this pathway unknown
  12. 2022 High

    Direct cholesterol binding by the amphipathic helix was biochemically demonstrated, and an unexpected pro-viral role for IFITM3 as an NTCP co-factor facilitating HBV/HDV entry was identified, showing that IFITM3 can promote or restrict virus entry depending on the pathogen.

    Evidence NBD-cholesterol binding assay with F63Q/F67Q mutants, MD simulations; membrane Y2H and Co-IP of IFITM3–NTCP, HBV/HDV infection assays in primary hepatocytes

    PMID:35458456 PMID:35872070

    Open questions at the time
    • Structural basis of cholesterol–AH interaction at atomic resolution unknown
    • Mechanism by which IFITM3 facilitates HBV/HDV post-attachment steps unclear
    • NTCP interaction not validated by reconstitution
  13. 2023 High

    Cryo-electron tomography captured IFITM3-mediated arrest of influenza fusion at the hemifusion diaphragm stage in situ, and PIP3 was identified as an interferon-inducible lipid rheostat required for endosomal IFITM restriction, unifying lipid sorting, hemifusion arrest, and phosphoinositide signaling into a coherent mechanistic model.

    Evidence In situ cryo-ET of IFITM3 KO versus WT cells infected with IAV; lipidomics, PIP3 supplementation, lysine mutants with pseudovirus and replicating virus assays

    PMID:36970857 PMID:37003257

    Open questions at the time
    • How IFITM3 recruits PIP3 to the hemifusion site at molecular detail unknown
    • Whether PIP3 rheostat applies to all restricted viruses not tested
    • No atomic-resolution structure of IFITM3 in a lipid bilayer
  14. 2025 Medium

    Cell-type-specific knockdown of IFITM3 in cerebrovascular endothelial cells reduced Aβ accumulation and improved cognition in AD mice, establishing a positive feedback loop between Aβ and IFITM3 and identifying vascular IFITM3 as a potential therapeutic target.

    Evidence AAV-BI30 endothelial IFITM3 knockdown in AD transgenic mice, BACE1/γ-secretase activity assays, behavioral and two-photon imaging

    PMID:39807629

    Open questions at the time
    • Molecular basis of IFITM3 regulation of BACE1 activity not determined
    • Whether endothelial IFITM3–Aβ feedback operates in human AD not tested
    • Single-lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of IFITM3 in native membranes, the precise mechanism by which IFITM3 suppresses phagosome maturation, the identity of the K88 methyltransferase, and how context-dependent phosphorylation, palmitoylation, ubiquitination, and methylation are integrated to switch IFITM3 between antiviral, signaling, and disease-promoting functions.
  • No high-resolution lipid bilayer structure
  • K88 methyltransferase unidentified
  • Integrated PTM cross-talk model not established
  • Cell-type-specific regulatory mechanisms incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 5 GO:0005764 lysosome 4 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2
Partners
AP2M1ITGA2BLSD1NEDD4NTCPVAPAVCPZDHHC20
Complex memberships
γ-secretase complex (functional interaction)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 IFITM3 antiviral activity is post-translationally regulated by S-palmitoylation on membrane-proximal cysteines, which controls its clustering in membrane compartments and its antiviral activity against influenza virus. Chemical reporter-based palmitoylome profiling, site-directed mutagenesis of cysteine residues, influenza virus infection assays Nature chemical biology High 20601941
2012 IFITM3 is essential for defending the host against influenza A virus in vivo; knockout mice develop fulminant viral pneumonia with a normally low-pathogenicity virus, and protection is rescued by re-introduction of Ifitm3. Knockout mouse model, viral challenge, in vitro complementation Nature High 22446628
2012 IFITM3 localizes to endolysosomes and prevents endocytosed virus particles from accessing the host cytoplasm; S-palmitoylation enhances membrane affinity and antiviral activity, while lysine ubiquitination decreases endolysosomal localization and antiviral activity. IFITM3 is proposed to adopt an intramembrane topology with both N and C termini facing the cytoplasm. Fluorescence imaging, cellular fractionation, N-linked glycosylation site insertion, protein lipidation mapping, mutagenesis The Journal of biological chemistry High 22511783
2012 The N-terminal 21-amino-acid region of IFITM3 is required for its endosomal localization and antiviral activity against pH-dependent viruses (influenza A); deletion of this region relocates IFITM3 to the cell periphery, abolishing restriction of pH-dependent viruses but not HIV-1. Deletion mutagenesis, subcellular localization imaging, viral infection assays Journal of virology High 23055554
2013 IFITM3 interacts with VAPA and prevents its association with OSBP, thereby disrupting intracellular cholesterol homeostasis; this induces cholesterol accumulation in multivesicular bodies and late endosomes, inhibiting fusion of virion-containing intraluminal vesicles with endosomal membranes and blocking virus release into the cytosol. Co-immunoprecipitation, ectopic expression/depletion of VAPA, cholesterol localization assays, viral entry assays Cell host & microbe High 23601107
2014 IFITM3 possesses a YxxΦ endocytic sorting motif (20-YEML-23) that enables it to undergo clathrin-mediated endocytosis through binding to the μ2 subunit of the AP-2 complex; blocking endocytosis of IFITM3 (by mutating this motif, depleting μ2, or overexpressing μ2 mutants) abrogates its antiviral activity against pH-dependent viruses. Mutagenesis of sorting motif, μ2 depletion/overexpression, subcellular localization imaging, viral infection assays Cellular microbiology High 24521078
2015 The E3 ubiquitin ligase NEDD4 ubiquitinates IFITM3 in cells and in vitro via interaction with a PPxY motif in IFITM3 and the WW domain of NEDD4; NEDD4 knockout leads to accumulation of IFITM3 and increased protection from influenza virus. Steady-state IFITM3 turnover occurs through the lysosomal degradation pathway. In vitro ubiquitination assay, NEDD4 knockout MEFs, PPxY motif mutagenesis, NEDD4 knockdown in human lung cells, lysosome inhibitor treatment PLoS pathogens High 26263374
2016 IFITM3 adopts a membrane topology with a single long transmembrane helix in the C-terminus and an intramembrane segment in the N-terminal hydrophobic region, with both termini facing the cytoplasm; this topology supports a mechanism of enhanced restricted membrane hemifusion. Systematic site-directed spin labeling (SDSL), EPR spectroscopy, solution NMR in detergent micelles Scientific reports High 27046158
2017 ZDHHC20 co-localizes with IFITM3 at lysosomes and uniquely enhances IFITM3 antiviral activity when both are overexpressed; multiple ZDHHCs (especially 3, 7, 15, 20) can palmitoylate IFITM3, demonstrating functional redundancy, and combined knockdown of ZDHHC3 and ZDHHC7 in ZDHHC20 KO cells decreases endogenous IFITM3 palmitoylation. ZDHHC knockout cell line screen, ZDHHC overexpression screen, co-localization imaging, palmitoylation assays, siRNA knockdown, viral infection assays The Journal of biological chemistry High 29079573
2017 LSD1 (a histone demethylase) is recruited to demethylate IFITM3 at position K88 under IFNα treatment, activating IFITM3; RNA virus infection (VSV or IAV) triggers IFITM3 K88 monomethylation by promoting IFITM3 dissociation from LSD1, and LSD1 inhibition increases IFITM3 monomethylation and worsens IAV infection in mice. In vitro demethylation assay, mutagenesis, LSD1 inhibitor treatment, mouse infection model, co-immunoprecipitation PLoS pathogens High 29281729
2019 IFITM3 is present on endocytic vesicles that fuse with incoming virus particles and enhances trafficking of viral cargo to lysosomes; this trafficking is specific to restricted viruses, requires S-palmitoylation, and is abrogated with loss-of-function mutants. CRISPR-Cas9 IFITM-mutant cell lines, site-specific fluorophore tagging, live-cell imaging, viral entry assays Nature chemical biology High 30643282
2020 IFITM3 binds to γ-secretase and upregulates its activity, thereby increasing amyloid-β production; inflammatory cytokines induce IFITM3 expression in neurons and astrocytes, and IFITM3 knockout reduces γ-secretase activity and amyloid plaque formation in 5xFAD mice. IFITM3 levels in the γ-secretase complex strongly correlate with γ-secretase activity in late-onset AD patient samples. Co-immunoprecipitation, IFITM3 KO mouse model (5xFAD), γ-secretase activity assays, human AD patient tissue analysis Nature High 32879487
2020 IFITM3 functions as a PIP3 scaffold at the plasma membrane to amplify PI3K signaling in B cells; oncogenic kinases phosphorylate IFITM3 at Tyr20, causing constitutive plasma membrane localization. IFITM3 uses Lys83 and Lys104 in its conserved intracellular loop as a scaffold for PIP3 accumulation. BCR engagement induces Tyr20 phosphorylation, switching IFITM3 from antiviral endosomal function to PI3K amplification at the cell surface. Phosphomimetic/phosphodeficient mutants, Ifitm3-/- mouse B cells, BCR signaling assays, lipid raft fractionation, PI3K signaling readouts, oncogene transformation assays Nature High 33149299
2020 VCP/p97 AAA-ATPase is a primary interaction partner of IFITM3; IFITM3 ubiquitination at lysine 24 is crucial for VCP binding, trafficking, turnover, and engagement with incoming virus particles. Pharmacological inhibition of VCP/p97 leads to defective IFITM3 lysosomal sorting and co-trafficking with virus particles. Site-specific photo-crosslinking, quantitative proteomics, mutagenesis (K24), VCP inhibitor treatment, lysosomal sorting assays, live-cell imaging Cell chemical biology High 32243810
2018 mTOR inhibition by rapamycin downregulates IFITM3 at the protein level (not mRNA) via a mechanism requiring endosomal trafficking, ubiquitination, ESCRT machinery, and lysosomal acidification, thereby promoting influenza A virus and lentiviral vector entry into cells. mTOR inhibitor treatment, IFITM3 siRNA/KO, ESCRT and lysosome inhibitors, virus infection assays, mRNA vs protein level analysis Proceedings of the National Academy of Sciences of the United States of America High 30301809
2020 IFITM3 oligomerization is driven by a GxxxG motif centered on Gly-95 (and Gly-91); mutation of Gly-95 disrupts IFITM3 oligomerization and reduces antiviral activity against influenza A virus. IFITM3 oligomers promote membrane rigidity in a Gly-95-dependent and amphipathic helix-dependent manner, and Amphotericin B counteracts this rigidification. Mutagenesis of GxxxG motif, oligomerization assays, membrane rigidity measurements, Amphotericin B treatment, influenza A virus infection assays eLife High 33112230
2022 The amphipathic helix (AH) of IFITM3 directly binds cholesterol; mutations F63Q and F67Q in the AH disrupt AH structure, inhibit cholesterol binding in vitro, restrict bilayer insertion in silico, and strongly impair antiviral function. Fluorescence-based in vitro cholesterol binding assay with NBD-cholesterol, AH mutagenesis, molecular dynamics simulation, antiviral assays Journal of molecular biology High 35872070
2023 IFITM3 induces local lipid sorting at the hemifusion site, increasing the concentration of fusion-disfavoring lipids, which raises the energy barrier for fusion pore formation and stabilizes hemifusion intermediates, causing viral degradation in lysosomes. In situ cryo-electron tomography captured IFITM3-mediated arrest of influenza A virus membrane fusion and hemifusion diaphragms at late endosomal membranes. In situ cryo-electron tomography, lipid analysis, hemifusion assays, IFITM3 KO cells, influenza A virus infection Cell host & microbe High 37003257
2010 IFITM3 disrupts an early event after endocytosis of VSV particles but before primary transcription of incoming viral genomes; both the N-terminal 21 amino acid residues and the C-terminal transmembrane region are required for antiviral activity. Viral infection assays (VSV), deletion mutagenesis, primary transcription assay Journal of virology Medium 20943977
2013 IFITM3 restricts reovirus entry in the endocytic pathway by modulating late endosomal compartment function; IFITM3 delays proteolytic processing of outer capsid protein μ1, suggesting it reduces endosomal protease activity or delays proteolysis. IFITM3 does not restrict reovirus ISVPs that bypass endosomal proteolysis. IFITM3-expressing cell lines, reovirus infection assays (ISVP vs intact virions), μ1 proteolysis assays, shRNA knockdown The Journal of biological chemistry Medium 23649619
2015 S-palmitoylation of IFITM1, IFITM2, and IFITM3 is essential for anti-HCV activity; a conserved tyrosine in the N-terminal domain of IFITM2 and IFITM3 regulates protein localization (to late and early endosomes, respectively) but is dispensable for anti-HCV activity. IFITM2 and IFITM3 act at late entry/endosomal stages of HCV infection. S-palmitoylation mutagenesis, tyrosine mutants, subcellular localization imaging, HCV infection assays The Journal of biological chemistry Medium 26354436
2011 KLF4 directly transcriptionally represses IFITM3 by binding to two KLF4-binding sites in the IFITM3 promoter; loss of KLF4 leads to IFITM3 overexpression in colon mucosa, and IFITM3 knockdown suppresses colon cancer cell proliferation, migration, and invasion. Chromatin immunoprecipitation, promoter mutagenesis, siRNA knockdown, villin-Cre conditional KLF4 KO mice, xenograft model Clinical cancer research Medium 21531817
2019 IFITM3 interacts with Smad4 and activates the TGF-β-Smads signaling pathway to promote prostate cancer cell proliferation, invasion, and bone migration; IFITM3 knockdown inhibits MAPK pathway activation induced by exogenous TGF-β. Co-immunoprecipitation (IFITM3-Smad4), shRNA knockdown, microarray, MAPK pathway assays Cell death & disease Low 31273201
2022 IFITM3 interacts with NTCP (the HBV/HDV receptor) and acts as an NTCP co-factor that facilitates HBV and HDV infection (not restriction) in a step subsequent to viral attachment; IFITM3 knockdown significantly reduces HBV and HDV infection of NTCP-expressing hepatocytes and primary human hepatocytes, while increasing influenza A virus infection. Membrane yeast-two-hybrid, co-immunoprecipitation, IFITM3 knockdown, HBV/HDV/IAV infection assays in HuH7-NTCP cells and primary hepatocytes Viruses Medium 35458456
2020 IFITM3 promotes fibrinogen endocytosis in megakaryocytes and platelets in an interferon-dependent manner; mechanistically, IFITM3 interacts with clathrin and αIIb and alters their plasma membrane localization into lipid rafts. IFITM3 is necessary and sufficient for fibrinogen endocytosis, and Ifitm3-/- mice are rescued from IFN-induced platelet hyperreactivity and thrombosis. Co-immunoprecipitation (IFITM3-clathrin-αIIb), Ifitm3-/- mouse model, IFITM3 overexpression/deletion in megakaryocytes, fibrinogen endocytosis assays, thrombosis assays The Journal of clinical investigation High 36194487
2021 IFITM3 is required for type I IFN-mediated suppression of phagosome maturation in macrophages; in the absence of IFITM3, phagosome maturation and proteolysis of Listeria virulence factors ActA and LLO are not suppressed, preventing phagosome escape. Ifitm3-/- mice are resistant to systemic Listeria infection. Ifitm3-/- mouse model, phagosome maturation assays, virulence factor proteolysis assays, bacterial infection assays Nature communications High 34404769
2020 p53 enhances IFITM3 palmitoylation by transcriptionally upregulating ZDHHC1, which interacts with IFITM3 to promote its palmitoylation and protein stability, thereby restricting Japanese encephalitis virus replication. JEV reduces p53 expression to impair this pathway. ZDHHC1 knockdown, p53 overexpression/knockdown, Co-IP (ZDHHC1-IFITM3), palmitoylation assays, viral replication assays PLoS pathogens Medium 33108395
2021 IFITM3 incorporation into IAV particles competes with viral hemagglutinin (HA) incorporation, reducing virion HA content; this sensitizes IAV to antibody-mediated neutralization, thereby impacting infection outcome in vivo. IFITM3 incorporation into virions, virion HA quantification, neutralization assays, mathematical modeling, mouse in vivo infection model The Journal of experimental medicine High 33882122
2023 PIP3 is required for endosomal IFITM restriction of viruses; lysines in the conserved IFITM intracellular loop recruit PIP3, and PIP3 acts as an interferon-inducible phospholipid rheostat for endosomal antiviral immunity. Plasma membrane-localized IFITM restriction operates independently of these lysines. Pseudotyped viral entry assays, replicating virus assays, high-throughput proteomics, lipidomics, IFITM mutants (lysine mutations), exogenous PIP3 supplementation The EMBO journal High 36970857
2022 IFITM3 directly interacts with the influenza HA2 subunit (but not HA1) via its transmembrane domain, as demonstrated by co-localization and co-immunoprecipitation; this interaction was confirmed across multiple influenza A subtypes and influenza B virus. Co-immunoprecipitation, subcellular co-localization, truncation/deletion analysis, pseudovirus entry assays Virologica Sinica Medium 35809785
2019 Small extracellular vesicles (sEVs) containing IFITM3 are partially responsible for transmitting paracrine senescence to normal neighboring cells; IFITM3 was identified by mass spectrometry proteomics of sEV cargo and confirmed by siRNA screen. Mass spectrometry proteomics, functional siRNA screen, Cre-reporter sEV uptake system Cell reports Medium 31242426
2009 IFITM3 physically interacts with osteopontin (OPN) in vitro and in vivo; IFITM3 expression reduces OPN mRNA expression (possibly via mRNA stability), and an IFITM3 DNA-binding domain mediates interaction with OPN. Stable IFITM3 transfection inhibits OPN-mediated anchorage-independent growth, cell adhesion, and invasion. Bacterial two-hybrid, in vitro binding, co-immunoprecipitation, antisense RNA, northern blot, stable transfection, invasion assays Oncogene Medium 19901966
2024 IFITM3 deficiency in FOXP3+ regulatory T cells enhances STAT1 translation and phosphorylation; conversely, STAT1 regulates IFITM3 expression forming a feedback loop. Blocking IFNγ or depleting the STAT1-IFITM3 axis phenocopies restored suppressive Treg function in tumors. IFITM3-deficient Treg mouse model, cytokine blocking, STAT1 KO, tumor growth assays, cytokine measurements Nature communications Medium 38167862
2025 IFITM3 in cerebrovascular endothelial cells (CVECs) regulates amyloid-β generation through BACE1 and γ-secretase; IFITM3 overexpression in endothelial cells enhances Aβ production, and Aβ further upregulates IFITM3 (positive feedback). AAV-mediated IFITM3 knockdown in CVECs reduces Aβ accumulation and improves cognition in AD transgenic mice. snRNA-seq, AAV-BI30 endothelial IFITM3 knockdown, BACE1/γ-secretase activity assays, behavioral tests, two-photon imaging, immunohistochemistry, Western blot Alzheimer's & dementia Medium 39807629

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 IFITM3 restricts the morbidity and mortality associated with influenza. Nature 622 22446628
2010 Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3. Nature chemical biology 312 20601941
2013 The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry. Cell host & microbe 296 23601107
2020 The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease. Nature 285 32879487
2010 Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. Journal of virology 261 20943977
2019 Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3. Cell reports 221 31242426
2019 IFITM3 directly engages and shuttles incoming virus particles to lysosomes. Nature chemical biology 192 30643282
2013 Enhanced survival of lung tissue-resident memory CD8⁺ T cells during infection with influenza virus due to selective expression of IFITM3. Nature immunology 191 23354485
2012 S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus. The Journal of biological chemistry 175 22511783
2012 The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization. Journal of virology 156 23055554
2019 Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3. Blood 148 30723081
2015 The Interferon-induced Transmembrane Proteins, IFITM1, IFITM2, and IFITM3 Inhibit Hepatitis C Virus Entry. The Journal of biological chemistry 148 26354436
2014 Identification of an endocytic signal essential for the antiviral action of IFITM3. Cellular microbiology 119 24521078
2013 IFITM-2 and IFITM-3 but not IFITM-1 restrict Rift Valley fever virus. Journal of virology 109 23720721
2011 KLF4-mediated negative regulation of IFITM3 expression plays a critical role in colon cancer pathogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 105 21531817
2015 E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3. PLoS pathogens 102 26263374
2013 Interferon-inducible transmembrane protein 3 (IFITM3) restricts reovirus cell entry. The Journal of biological chemistry 101 23649619
2016 Natural mutations in IFITM3 modulate post-translational regulation and toggle antiviral specificity. EMBO reports 93 27601221
2017 The palmitoyltransferase ZDHHC20 enhances interferon-induced transmembrane protein 3 (IFITM3) palmitoylation and antiviral activity. The Journal of biological chemistry 88 29079573
2020 IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 87 33149299
2016 The Interferon-Stimulated Gene Ifitm3 Restricts West Nile Virus Infection and Pathogenesis. Journal of virology 83 27384652
2018 mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3. Proceedings of the National Academy of Sciences of the United States of America 74 30301809
2018 Antiviral Protection by IFITM3 In Vivo. Current clinical microbiology reports 71 30662816
2020 The Interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19. Cytokine 67 33113474
2023 IFITM3 blocks influenza virus entry by sorting lipids and stabilizing hemifusion. Cell host & microbe 65 37003257
2014 Regulation of the trafficking and antiviral activity of IFITM3 by post-translational modifications. Future microbiology 65 25405885
2020 Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state. eLife 63 33112230
2013 Defining the range of pathogens susceptible to Ifitm3 restriction using a knockout mouse model. PloS one 62 24278312
2020 Interferon-Induced Transmembrane Protein (IFITM3) Is Upregulated Explicitly in SARS-CoV-2 Infected Lung Epithelial Cells. Frontiers in immunology 55 32595654
2019 IFITM3 promotes bone metastasis of prostate cancer cells by mediating activation of the TGF-β signaling pathway. Cell death & disease 54 31273201
2017 Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection. The Journal of infectious diseases 54 28531322
1999 Interferon-inducible gene family 1-8U expression in colitis-associated colon cancer and severely inflamed mucosa in ulcerative colitis. Cancer research 50 10606237
2016 Combined approaches of EPR and NMR illustrate only one transmembrane helix in the human IFITM3. Scientific reports 49 27046158
2017 The V3 Loop of HIV-1 Env Determines Viral Susceptibility to IFITM3 Impairment of Viral Infectivity. Journal of virology 48 28100616
2021 The influence of IFITM3 polymorphisms on susceptibility to SARS-CoV-2 infection and severity of COVID-19. Cytokine 46 33711707
2024 FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity. Nature communications 45 38167862
2020 Bat SARS-Like WIV1 coronavirus uses the ACE2 of multiple animal species as receptor and evades IFITM3 restriction via TMPRSS2 activation of membrane fusion. Emerging microbes & infections 45 32602823
2016 Constitutively Expressed IFITM3 Protein in Human Endothelial Cells Poses an Early Infection Block to Human Influenza Viruses. Journal of virology 44 27707929
2020 Malignancy and IFITM3: Friend or Foe? Frontiers in oncology 41 33364194
2018 IFITM3 promotes hepatocellular carcinoma invasion and metastasis by regulating MMP9 through p38/MAPK signaling. FEBS open bio 41 30087833
2019 IFITM3: How genetics influence influenza infection demographically. Biomedical journal 38 30987701
2018 Lack of Truncated IFITM3 Transcripts in Cells Homozygous for the rs12252-C Variant That is Associated With Severe Influenza Infection. The Journal of infectious diseases 38 29202190
2018 IFITM3 Restricts Human Metapneumovirus Infection. The Journal of infectious diseases 37 29917090
2013 The role of IFITM3 in the growth and migration of human glioma cells. BMC neurology 37 24370119
2020 IFITM3 Reduces Retroviral Envelope Abundance and Function and Is Counteracted by glycoGag. mBio 36 31964738
2014 Mechanism and biological significance of the overexpression of IFITM3 in gastric cancer. Oncology reports 36 25270246
2003 Inhibition of proliferation by 1-8U in interferon-alpha-responsive and non-responsive cell lines. Cellular and molecular life sciences : CMLS 36 12861389
2023 Interferon-induced transmembrane protein 3 (IFITM3) limits lethality of SARS-CoV-2 in mice. EMBO reports 35 36880581
2022 IFITM3 regulates fibrinogen endocytosis and platelet reactivity in nonviral sepsis. The Journal of clinical investigation 35 36194487
2020 EVs Containing Host Restriction Factor IFITM3 Inhibited ZIKV Infection of Fetuses in Pregnant Mice through Trans-placenta Delivery. Molecular therapy : the journal of the American Society of Gene Therapy 35 33002418
2019 Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain. Life science alliance 35 31826928
2023 Aβ Induces Neuroinflammation and Microglial M1 Polarization via cGAS-STING-IFITM3 Signaling Pathway in BV-2 Cells. Neurochemical research 33 37210413
2019 IFITM3 knockdown reduces the expression of CCND1 and CDK4 and suppresses the growth of oral squamous cell carcinoma cells. Cellular oncology (Dordrecht, Netherlands) 33 30949979
2018 Association between IFITM3 rs12252 polymorphism and influenza susceptibility and severity: A meta-analysis. Gene 33 29940276
2017 Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation. PLoS pathogens 32 29281729
2020 Site-Specific Photo-Crosslinking Proteomics Reveal Regulation of IFITM3 Trafficking and Turnover by VCP/p97 ATPase. Cell chemical biology 31 32243810
2015 Respiratory DC Use IFITM3 to Avoid Direct Viral Infection and Safeguard Virus-Specific CD8+ T Cell Priming. PloS one 31 26600246
2022 Cholesterol Binds the Amphipathic Helix of IFITM3 and Regulates Antiviral Activity. Journal of molecular biology 30 35872070
2022 IFITM3 Inhibits SARS-CoV-2 Infection and Is Associated with COVID-19 Susceptibility. Viruses 30 36423162
2019 Rapid interferon independent expression of IFITM3 following T cell activation protects cells from influenza virus infection. PloS one 30 30650117
2018 miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3. Oncology reports 30 30272306
2020 The frequency of combined IFITM3 haplotype involving the reference alleles of both rs12252 and rs34481144 is in line with COVID-19 standardized mortality ratio of ethnic groups in England. PeerJ 29 33240681
2011 Identification of the IFITM3 gene as an inhibitor of hepatitis C viral translation in a stable STAT1 cell line. Journal of viral hepatitis 28 21914072
2010 Identification of the polymorphisms in IFITM3 gene and their association in a Korean population with ulcerative colitis. Experimental & molecular medicine 28 19946179
2019 IFITM3 Clusters on Virus Containing Endosomes and Lysosomes Early in the Influenza A Infection of Human Airway Epithelial Cells. Viruses 26 31212878
2022 IFITM3 promotes malignant progression, cancer stemness and chemoresistance of gastric cancer by targeting MET/AKT/FOXO3/c-MYC axis. Cell & bioscience 25 35941699
2020 Exosomes released by imatinib‑resistant K562 cells contain specific membrane markers, IFITM3, CD146 and CD36 and increase the survival of imatinib‑sensitive cells in the presence of imatinib. International journal of oncology 25 33491750
2019 IFITM3/STAT3 axis promotes glioma cells invasion and is modulated by TGF-β. Molecular biology reports 25 31637620
2022 Increased Expression of Interferon-Induced Transmembrane 3 (IFITM3) in Stroke and Other Inflammatory Conditions in the Brain. International journal of molecular sciences 23 36012150
2022 IFITM3 Interacts with the HBV/HDV Receptor NTCP and Modulates Virus Entry and Infection. Viruses 22 35458456
2022 Increased risk of COVID-19 mortality rate in IFITM3 rs6598045 G allele carriers infected by SARS-CoV-2 delta variant. Human genomics 22 36403064
2021 Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes. Nature communications 22 34404769
2019 IFITM3 upregulates c-myc expression to promote hepatocellular carcinoma proliferation via the ERK1/2 signalling pathway. Bioscience trends 22 31852866
2017 Chemical Synthesis of the Highly Hydrophobic Antiviral Membrane-Associated Protein IFITM3 and Modified Variants. Angewandte Chemie (International ed. in English) 22 28834009
2013 A functional promoter polymorphism of IFITM3 is associated with susceptibility to pediatric tuberculosis in Han Chinese population. PloS one 22 23874452
2021 IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization. The Journal of experimental medicine 21 33882122
2023 Interferon-inducible phospholipids govern IFITM3-dependent endosomal antiviral immunity. The EMBO journal 20 36970857
2017 Population genetics of IFITM3 in Portugal and Central Africa reveals a potential modifier of influenza severity. Immunogenetics 20 28842783
2022 Interferon-induced transmembrane protein 3 (IFITM3) and its antiviral activity. Current opinion in structural biology 19 36306674
2021 Human IFITM3 restricts chikungunya virus and Mayaro virus infection and is susceptible to virus-mediated counteraction. Life science alliance 19 34078739
2024 IFITM3 promotes glioblastoma stem cell-mediated angiogenesis via regulating JAK/STAT3/bFGF signaling pathway. Cell death & disease 18 38218875
2022 The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: A systematic review and meta-analysis. EXCLI journal 18 35949487
2020 The Robust Restriction of Zika Virus by Type-I Interferon in A549 Cells Varies by Viral Lineage and Is Not Determined by IFITM3. Viruses 18 32370187
2020 p53 promotes ZDHHC1-mediated IFITM3 palmitoylation to inhibit Japanese encephalitis virus replication. PLoS pathogens 18 33108395
2020 Ethnic variation in risk genotypes based on single nucleotide polymorphisms (SNPs) of the interferon-inducible transmembrane 3 (IFITM3) gene, a susceptibility factor for pandemic 2009 H1N1 influenza A virus. Immunogenetics 17 33174121
2019 HA-Dependent Tropism of H5N1 and H7N9 Influenza Viruses to Human Endothelial Cells Is Determined by Reduced Stability of the HA, Which Allows the Virus To Cope with Inefficient Endosomal Acidification and Constitutively Expressed IFITM3. Journal of virology 17 31597765
2013 Widespread but tissue-specific patterns of interferon-induced transmembrane protein 3 (IFITM3, FRAGILIS, MIL-1) in the mouse gastrula. Gene expression patterns : GEP 17 23639725
2021 TUG1 promotes the expression of IFITM3 in hepatocellular carcinoma by competitively binding to miR-29a. Journal of Cancer 16 34659578
2020 miR-152-3p Affects the Progression of Colon Cancer via the KLF4/IFITM3 Axis. Computational and mathematical methods in medicine 16 32952601
2009 Interferon-induced transmembrane 3 binds osteopontin in vitro: expressed in vivo IFITM3 reduced OPN expression. Oncogene 16 19901966
2025 Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer's-related phenotypes. Alzheimer's & dementia : the journal of the Alzheimer's Association 14 39807629
2024 Innate immune control of influenza virus interspecies adaptation via IFITM3. Nature communications 14 39477971
2022 MiR-487b suppressed inflammation and neuronal apoptosis in spinal cord injury by targeted Ifitm3. Metabolic brain disease 14 35802304
2021 HCMV infection and IFITM3 rs12252 are associated with Rasmussen's encephalitis disease progression. Annals of clinical and translational neurology 14 33465303
2021 Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease. Brain, behavior, & immunity - health 14 33817671
2020 Comprehensive analysis of two potential novel SARS-CoV-2 entries, TMPRSS2 and IFITM3, in healthy individuals and cancer patients. International journal of biological sciences 14 33061814
2024 LPS-induced senescence of macrophages aggravates calcification and senescence of vascular smooth muscle cells via IFITM3. Renal failure 13 38973391
2020 Escape of HIV-1 envelope glycoprotein from the restriction of infection by IFITM3. Journal of virology 13 33298540
2022 Transmembrane domain of IFITM3 is responsible for its interaction with influenza virus HA2 subunit. Virologica Sinica 12 35809785
2017 Association of IFITM3 rs12252 polymorphisms, BMI, diabetes, and hypercholesterolemia with mild flu in an Iranian population. Virology journal 12 29121968