{"gene":"HAVCR1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1998,"finding":"Human HAVCR1 (huhavcr-1) encodes a 359-amino-acid class I integral-membrane mucin-like glycoprotein that functions as a binding and functional receptor for hepatitis A virus (HAV); dog cells transfected with huHAVcr-1 cDNA bound HAV and gained susceptibility to HAV infection.","method":"cDNA transfection into receptor-negative dog cells, HAV binding assay, infection susceptibility assay, MAb blocking experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution in receptor-negative cells with direct virus binding and infection readout","pmids":["9658108"],"is_preprint":false},{"year":2007,"finding":"TIM-1 (HAVCR1) specifically binds phosphatidylserine (PS) on the surface of apoptotic cells (but not other phospholipids), and TIM-1-expressing cells efficiently phagocytose apoptotic cells; mutations in the unique IgV cavity of TIM-1 eliminated PS binding and phagocytosis.","method":"Phospholipid binding assay, phagocytosis assay with transfected cells and primary kidney cells, MAb blocking, site-directed mutagenesis of PS-binding cavity","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding reconstitution, mutagenesis, and functional phagocytosis assay in multiple cell types","pmids":["18082433"],"is_preprint":false},{"year":2005,"finding":"TIM-1 functions as a T cell costimulatory molecule expressed on activated CD4+ T cells; TIM-1-specific MAb ligation plus TCR stimulation enhanced T cell proliferation and IL-4 production preferentially in Th2 cells; in vivo TIM-1 ligation prevented respiratory tolerance.","method":"Anti-TIM-1 mAb stimulation of purified CD4+ T cells in vitro, cytokine ELISA, in vivo antigen + anti-TIM-1 treatment with pulmonary inflammation readout","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vitro costimulation, in vivo tolerance model) with specific functional readouts","pmids":["15793575"],"is_preprint":false},{"year":2007,"finding":"Human TIM-1 associates with the TCR-signaling complex via CD3, upregulates phosphorylation of Zap70 and ITK, requires TIM-1 tyrosine phosphorylation for this activity, and induces formation of a novel complex including PI3K and ITK, leading to increased effector cytokine expression.","method":"Co-immunoprecipitation, phosphorylation assays, complex formation analysis in T cells, cytokine production assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with mechanistic follow-up (phosphorylation, complex formation, tyrosine requirement), multiple methods","pmids":["17371991"],"is_preprint":false},{"year":2013,"finding":"TIM-1 mediates enveloped virus entry via apoptotic mimicry: key PS-binding residues in the IgV domain are critical for Ebola virus (EBOV) entry through direct interaction with PS on the viral envelope; PS liposomes competed with TIM-1 for EBOV pseudovirion binding; TIM-1 enhanced infection of a broad range of enveloped viruses including alphaviruses, and mediated glycoprotein-independent virus uptake.","method":"Pseudovirion transduction assay, PS liposome competition, site-directed mutagenesis of PS-binding pocket, annexin V substitution experiments, virus-like particle uptake assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of active site plus multiple functional assays and competition experiments","pmids":["23698310"],"is_preprint":false},{"year":2007,"finding":"TIM-1 is an endogenous ligand for the activating myeloid receptor LMIR5/CD300b; the Ig-like domain of LMIR5 binds TIM-1 near its PS-binding site; TIM-1 stimulation activates mast cells via LMIR5; TIM-1–LMIR5 interaction promotes neutrophil recruitment in vivo.","method":"Retrovirus-mediated expression cloning, protein binding assays, mast cell activation assay, in vivo neutrophil recruitment model, LMIR5 knockout mice","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — expression cloning identification, binding domain mapping, and in vivo functional validation with knockout mice","pmids":["20566714"],"is_preprint":false},{"year":2015,"finding":"KIM-1/TIM-1-mediated phagocytosis of apoptotic cells requires KIM-1 phosphorylation and association with p85 (PI3K regulatory subunit), leading to LC3 lipidation and phagosome encapsulation; autophagy genes (ATG5, ULK1) are required for efficient apoptotic cell clearance and phagosome maturation; KIM-1-mediated phagocytosis promotes pro-tolerogenic antigen presentation that suppresses CD4 T-cell proliferation and increases regulatory T cells.","method":"Co-immunoprecipitation (KIM-1/p85), LC3 lipidation assay, ROS measurement, NOX inhibition, autophagy gene KO, antigen presentation assay, T cell proliferation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including Co-IP, genetic KO of autophagy genes, and functional immune readouts","pmids":["26282792"],"is_preprint":false},{"year":2015,"finding":"TIM-1 signaling in regulatory B cells (Bregs) is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production; TIM-1 mucin domain mutant mice (TIM-1Δmucin) show decreased PS binding and fail to produce IL-10 in response to ACs or TIM-1 ligation, and exhibit accelerated allograft rejection; transfer of WT TIM-1+ B cells restores graft survival.","method":"Loss-of-function mucin-domain mutant knock-in mice, apoptotic cell binding assay, IL-10 production assay, allograft rejection model, B cell adoptive transfer","journal":"American journal of transplantation","confidence":"High","confidence_rationale":"Tier 2 — domain-specific knock-in mutant with multiple functional readouts and rescue by adoptive transfer","pmids":["25645598"],"is_preprint":false},{"year":2009,"finding":"IgA is a natural ligand of HAVCR1/TIM-1; IgA binds specifically to TIM-1 via the IgV domain; the IgA and HAV binding sites on HAVCR1 are distinct epitopes; IgA association with HAVCR1 synergistically enhances HAV neutralization by HAVCR1-Fc fusion protein.","method":"Expression cloning of cDNA library with HAVCR1-Fc fusion protein, ELISA binding assay, MAb blocking, HAV neutralization assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — expression cloning plus binding and functional neutralization assays from single study","pmids":["17229699"],"is_preprint":false},{"year":2014,"finding":"TIM-1 glycoprotein is a P-selectin ligand; the TIM-1 mucin domain mediates tethering and rolling of Th1 and Th17 cells on P-selectin, and the IgV domain is also required for P-selectin binding; Th1/Th17 cells lacking TIM-1 mucin domain show reduced rolling in inflamed venules; TIM-1 blockade reduces T cell recruitment in skin hypersensitivity and blocks EAE.","method":"Binding assay (human and murine TIM-1 to P-selectin), intravital microscopy of mesenteric venules and brain microcirculation, mucin-domain-deleted mutant mice, skin hypersensitivity and EAE models","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay, domain-deletion mutant, intravital microscopy, and multiple in vivo disease models","pmids":["24703780"],"is_preprint":false},{"year":2015,"finding":"Phosphatidylethanolamine (PE) is a ligand for TIM-1; TIM-1 efficiently binds PE present on viral envelopes (West Nile, dengue, Ebola virions); PE on apoptotic cells promotes phagocytic uptake by TIM-1-expressing cells; the PE-binding cyclic peptide Duramycin blocks TIM-1-mediated (but not L-SIGN-mediated) virus entry by blocking virus attachment to TIM-1.","method":"Phospholipid binding assay, pseudovirus infection assay, Duramycin competition assay, phagocytosis assay, apoptotic cell PE exposure measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct binding, specific inhibition with PE-blocking compound, and multiple virus entry assays","pmids":["26575624"],"is_preprint":false},{"year":2015,"finding":"TIM-1 and NPC1 colocalize and physically interact in intracellular vesicles where EBOV glycoprotein-mediated membrane fusion occurs; a TIM-1-specific mAb (M224/1) blocked GP-mediated fusion and interfered with TIM-1–NPC1 binding, demonstrating that the TIM-1–NPC1 interaction is required for filovirus membrane fusion.","method":"Co-localization (immunofluorescence), Co-immunoprecipitation/binding assay, mAb blocking of fusion and protein–protein interaction, pseudovirus infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus functional blockade with mechanistic antibody, replicated across multiple filovirus species","pmids":["25855742"],"is_preprint":false},{"year":2015,"finding":"TIM-1 directly interacts with EBOV glycoprotein (GP) in addition to binding PS on the viral envelope; crystal structures of hTIM-1 and hTIM-4 IgV domains were determined; chimeric and point-mutant analyses mapped the GP-binding region on hTIM-1 distinct from the PS-binding site.","method":"In vitro direct binding assay (TIM-1/EBOV GP), X-ray crystallography, chimeric protein construction, site-directed mutagenesis, pseudovirion infection assay","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro binding, mutagenesis, and functional infection assay","pmids":["26487564"],"is_preprint":false},{"year":2018,"finding":"TIM-1 is an authentic DENV entry receptor that is co-internalized with DENV in clathrin-coated pits; TIM-1 is ubiquitinated at two cytoplasmic lysine residues, and this ubiquitination is required for DENV endocytosis; STAM-1 (ESCRT-0 component) interacts with TIM-1 and is required for DENV infection.","method":"CRISPR/Cas9 TIM-1 KO, TIRF live-cell microscopy, ubiquitination assay, lysine mutagenesis, STAM-1 Co-IP, siRNA knockdown","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO, live imaging, ubiquitination site mapping by mutagenesis, and Co-IP, multiple orthogonal methods","pmids":["29742433"],"is_preprint":false},{"year":2011,"finding":"Fyn kinase (Src family) physically associates with TIM-1 and is required for phosphorylation of the conserved tyrosine in the TIM-1 cytoplasmic tail; Fyn–TIM-1 association does not require Fyn kinase activity; TIM-1 tyrosine phosphorylation level varies with Fyn expression.","method":"Co-immunoprecipitation, kinase-dead Fyn mutant, phosphorylation assay, Fyn expression modulation","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with mechanistic follow-up (kinase-dead mutant, phosphorylation assay), single lab","pmids":["21513984"],"is_preprint":false},{"year":2009,"finding":"TIM-1 ligation induces polyclonal T cell activation independently of conventional TCR signal 1, requiring strong costimulation from mature dendritic cells; TIM-1 stimulation raises free cytosolic calcium, triggers calcineurin-dependent NF-AT nuclear translocation, and induces IL-2 transcription; TIM-4 on mature DCs serves as the TIM-1 counter-receptor.","method":"Anti-TIM-1 mAb stimulation in vitro, calcium flux assay, NF-AT translocation assay, IL-2 reporter, calcineurin inhibitor","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling readouts (Ca2+, NF-AT, IL-2) with pharmacologic inhibition, single lab","pmids":["19155484"],"is_preprint":false},{"year":2017,"finding":"EBOV directly binds primary T lymphocytes in a phosphatidylserine–TIM-1-dependent manner (without detectable viral replication), causing rapid non-antigen-specific T cell activation, cytokine production, and a cytokine storm-like phenomenon; TIM-1 knockout mice show increased survival and reduced inflammatory response after EBOV challenge with only modest reduction in viremia.","method":"TIM-1 KO mice EBOV challenge, in vitro EBOV binding assay with primary T cells, flow cytometry (CD4Hi CD3Low population), cytokine/chemokine measurement, transcriptome analysis, Western blot","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — KO mice plus multiple in vitro mechanistic assays (binding, activation, transcriptomics), orthogonal methods","pmids":["28951472"],"is_preprint":false},{"year":2020,"finding":"HAVCR1 and NPC1 both participate in clathrin-mediated endocytosis and membrane fusion of exosome-associated HAV (exo-HAV); CRISPR-Cas9 knockout of either HAVCR1 or NPC1 blocks membrane fusion and cytoplasmic RNA delivery from exo-HAV; the HAVCR1–NPC1 pathway mediates HAV infection via exosome mimicry without requiring an envelope glycoprotein.","method":"CRISPR/Cas9 knockout of HAVCR1 and NPC1, membrane fusion assay, RNA delivery assay, methylene blue inactivation of non-encapsidated RNA","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR KO with direct functional assays for fusion and RNA delivery, two receptor KOs tested","pmids":["32541946"],"is_preprint":false},{"year":2018,"finding":"HAVCR1 and its mouse ortholog are functional HAV receptors: CRISPR/Cas9 knockout of monkey HAVCR1 in AGMK cells abolishes susceptibility to both naked HAV and exo-HAV infection; transfection of HAVCR1 or mouse mHavcr1 cDNA into KO cells restores susceptibility.","method":"CRISPR/Cas9 KO, cDNA rescue (HAVCR1 and mHavcr1 transfection), HAV infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — genetic KO with full rescue by receptor cDNA, definitive functional reconstitution","pmids":["29437974"],"is_preprint":false},{"year":2017,"finding":"TIM-1 promotes HCV infection by serving as an attachment receptor that binds PS exposed on the HCV envelope; TIM-1 KO in Huh-7.5 cells reduces HCV cell attachment and infection; ectopic TIM-1 (but not TIM-3 or TIM-4) rescues infection; PS liposomes block HCV attachment and infection; HCV particles could be immunoprecipitated with PS-specific antibody.","method":"CRISPR/Cas9 TIM-1 KO, ectopic expression rescue, PS liposome competition, anti-PS immunoprecipitation of HCV particles, siRNA knockdown","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — KO with specific rescue, competition assay, and immunoprecipitation of virus–PS complex","pmids":["27807228"],"is_preprint":false},{"year":2014,"finding":"HAVCR1/KIM-1 activates the IL-6/STAT-3/HIF-1A signaling axis in clear cell renal cell carcinoma; this activation depends on HAVCR1 ectodomain shedding, as determined by microarray analysis of cells with upregulated or silenced HAVCR1.","method":"HAVCR1 overexpression and siRNA silencing, microarray, STAT-3 phosphorylation assay, HIF-1A measurement, ectodomain shedding assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with signaling pathway readout, single lab","pmids":["24390735"],"is_preprint":false},{"year":2011,"finding":"TIM-1 signaling in dendritic cells upregulates costimulatory molecule expression and proinflammatory cytokine production, promoting effector T cell responses while inhibiting Foxp3+ Treg responses; high-avidity anti-TIM-1 antibody enhances DC immunogenic function and promotes Th17 responses in vivo.","method":"Anti-TIM-1 mAb stimulation of DCs, flow cytometry (costimulatory molecules), cytokine measurement, in vivo EAE model with high- vs. low-avidity antibodies","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro DC activation plus in vivo disease model, single lab","pmids":["21469101"],"is_preprint":false},{"year":2009,"finding":"HAV interaction with soluble HAVCR1 requires calcium (not replaceable by Li, Na, Mg, Mn, or Zn), is temperature-dependent (faster at 37°C than 4°C), and occurs at pH 5–8 (most efficient pH 6–7); soluble HAVCR1 neutralizes wild-type HAV, confirming the receptor's role in authentic virus entry.","method":"Soluble receptor neutralization and alteration assays, ion substitution experiments, temperature and pH variation, wt HAV cell culture system","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical characterization of receptor–virus interaction with multiple conditions tested","pmids":["19860892"],"is_preprint":false},{"year":2011,"finding":"TIM-1 is expressed on mast cells and its ligation by TIM-4 (its ligand on DCs) promotes IL-4, IL-6, and IL-13 production without enhancing degranulation in IgE+Ag-stimulated mast cells.","method":"Flow cytometry (TIM-1/TIM-3 expression on mast cells), recombinant TIM-4 stimulation of bone marrow-derived mast cells, cytokine ELISA, degranulation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — direct ligand stimulation with specific cytokine and degranulation readouts","pmids":["17620455"],"is_preprint":false},{"year":2022,"finding":"KIM-1/TIM-1 is a receptor for SARS-CoV-2 in lung and kidney epithelial cells; KIM-1-expressing cells that lack ACE2 are permissive to SARS-CoV-2 infection; KIM-1 binds the SARS-CoV-2 Spike protein in vitro; anti-KIM-1 antibodies and TW-37 inhibit KIM-1-mediated uptake of Spike-displaying virosomes.","method":"In vitro Spike protein binding assay, nanoparticle/virosome uptake assay, anti-KIM-1 antibody blocking, SARS-CoV-2 infection of KIM-1-expressing/ACE2-negative cells, TW-37 inhibition","journal":"medRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding plus functional infection with ACE2-negative cells, preprint","pmids":["32995803"],"is_preprint":true},{"year":2018,"finding":"TIM-1 mediates dystroglycan-independent entry of Lassa virus (LASV) pseudovirions through interaction of virion-associated PtdSer with the IgV PtdSer-binding pocket of TIM-1; mutagenesis of PS-binding pocket abrogates transduction; chimeric TIM-1 lacking the mucin domain but retaining the IgV domain is competent as a receptor.","method":"CRISPR/Cas9 αDG knockout, pseudovirus transduction assay, IgV domain mutagenesis, mAb ARD5 blocking assay, chimeric TIM-1 rescue","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of functional domain with specific rescue, multiple conditions tested","pmids":["29875238"],"is_preprint":false},{"year":2019,"finding":"TIM-1 promotes DENV-induced autophagy as a signaling receptor: TIM-1 colocalizes with autophagosomes during DENV infection (co-transported with virus); TIM-1 knockdown reduces both DENV internalization and autophagy activation; TIM-1-mediated autophagy requires p85 (PI3K subunit), which co-localizes with TIM-1 at Rab5-positive endosomes.","method":"Confocal microscopy (TIM-1/autophagosome co-localization), siRNA knockdown of TIM-1 and p85, GFP-LC3 autophagy reporter, co-localization at Rab5 endosomes","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — co-localization plus siRNA knockdown with mechanistic pathway (PI3K/p85) identification","pmids":["31581681"],"is_preprint":false},{"year":2018,"finding":"Semaphorin 4A (Sema4A) and H-ferritin utilize TIM-1 on human oligodendrocytes: TIM-1 mediates Sema4A-induced apoptosis and H-ferritin uptake (iron delivery) in human oligodendrocytes; H-ferritin can block Sema4A-mediated cytotoxicity via TIM-1.","method":"TIM-1 expression in human oligodendrocytes, Sema4A apoptosis assay, H-ferritin uptake assay, TIM-1 blocking experiments","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 — direct receptor identification with functional apoptosis and iron uptake readouts, single lab","pmids":["29457657"],"is_preprint":false},{"year":2012,"finding":"Epsilon toxin from Clostridium perfringens binds HAVCR1 as a cell surface receptor; aromatic amino acids Y29, Y30, Y36, and Y196 in the toxin are critical for binding to HAVCR1 and host cells; mutant toxins (e.g., Etx-Y29E) are defective in HAVCR1 binding, cell binding, and cytotoxic activity.","method":"Site-directed mutagenesis of epsilon toxin, cell binding assay, HAVCR1 binding assay, cytotoxicity assay, circular dichroism spectroscopy","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of toxin binding determinants with functional cell and receptor binding readouts","pmids":["22938730"],"is_preprint":false},{"year":2011,"finding":"TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation into plasma cells; anti-TIM-1 mAb stimulation of activated B cells increased IgG2b and IgG3 secretion in vitro; in vivo TIM-1 ligation increased OVA-specific IgG2b, IgG3, and IgE in immunized mice.","method":"Anti-TIM-1 mAb stimulation of activated B cells, proliferation assay, syndecan-1 (CD138) expression, antibody ELISA, in vivo immunization with T-dependent and T-independent antigens","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo functional assays, single lab","pmids":["21303660"],"is_preprint":false},{"year":2022,"finding":"TIM-1 regulates STAT3 signaling in regulatory B cells and modulates their suppressive function; CRISPR-mediated TIM-1 deletion demonstrates predominant roles for TIM-1 (and CD154) in expBreg-mediated suppressive function that is only partially IL-10-dependent.","method":"CRISPR-mediated gene deletion in human expanded B cells, STAT3 signaling assay, T cell suppression assay, humanized mouse skin transplant model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with signaling pathway readout and in vivo transplant model, single lab","pmids":["35660734"],"is_preprint":false}],"current_model":"HAVCR1/TIM-1 is a type I transmembrane mucin-like glycoprotein that acts as a phosphatidylserine (and phosphatidylethanolamine) receptor mediating phagocytosis of apoptotic cells, broad enveloped-virus entry via apoptotic mimicry, and T/B cell costimulation: its IgV domain PS-binding cavity is required for apoptotic cell clearance, filovirus/flavivirus/arenavirus entry, and regulatory B cell IL-10 production; its cytoplasmic tail undergoes Fyn-dependent tyrosine phosphorylation and ubiquitination that drives clathrin/ESCRT-dependent endocytosis; it associates with CD3/TCR complex to amplify Zap70/ITK/PI3K signaling in T cells; it binds P-selectin via its mucin domain to mediate Th1/Th17 trafficking; and it interacts with NPC1 in endosomes to enable membrane fusion during viral and exosomal cargo delivery."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of HAVCR1 as the functional cellular receptor for hepatitis A virus established the gene as a virus entry factor and defined its basic topology as a type I integral-membrane mucin-like glycoprotein.","evidence":"cDNA transfection into receptor-negative dog cells conferring HAV binding and infection","pmids":["9658108"],"confidence":"High","gaps":["Mechanism of HAV internalization unknown","No knowledge of non-viral ligands or immune function"]},{"year":2005,"claim":"Demonstrating that TIM-1 ligation costimulates T cell activation and Th2 cytokine production revealed a second, immune-regulatory role beyond virus entry.","evidence":"Anti-TIM-1 mAb costimulation of purified CD4+ T cells plus in vivo tolerance model","pmids":["15793575"],"confidence":"High","gaps":["Signaling pathway downstream of TIM-1 in T cells unknown","Natural ligand for costimulatory function not identified"]},{"year":2007,"claim":"Discovery that TIM-1 binds phosphatidylserine through a unique IgV cavity and mediates phagocytosis of apoptotic cells unified its viral and immune functions under a single PS-recognition mechanism.","evidence":"Phospholipid binding assays, site-directed mutagenesis of PS-binding cavity, phagocytosis reconstitution in transfected and primary kidney cells","pmids":["18082433"],"confidence":"High","gaps":["Whether PS binding accounts for all viral entry or additional receptor–ligand contacts exist","Downstream signaling from PS engagement uncharacterized"]},{"year":2007,"claim":"Mapping TIM-1 association with the CD3/TCR complex and identification of Zap70/ITK/PI3K phosphorylation cascade explained how TIM-1 amplifies T cell activation at a molecular level.","evidence":"Co-immunoprecipitation of TIM-1 with CD3, phosphorylation assays for Zap70 and ITK, tyrosine-mutant analysis","pmids":["17371991"],"confidence":"High","gaps":["Identity of the kinase phosphorylating TIM-1 cytoplasmic tail unknown","Structural basis of TIM-1–CD3 association not resolved"]},{"year":2009,"claim":"Showing that TIM-1 ligation induces calcium flux, NF-AT nuclear translocation, and IL-2 transcription linked TIM-1 to the canonical calcineurin/NF-AT pathway, and identified TIM-4 on DCs as a counter-receptor.","evidence":"Calcium flux assay, NF-AT translocation, calcineurin inhibitor blockade, IL-2 reporter in stimulated T cells","pmids":["19155484"],"confidence":"Medium","gaps":["Whether TIM-4 is the sole physiological ligand for costimulation","Relative contribution of PS-binding versus protein–protein interaction with TIM-4 unclear"]},{"year":2011,"claim":"Identification of Fyn kinase as the Src-family kinase that physically associates with and phosphorylates the TIM-1 cytoplasmic tyrosine resolved the proximal signaling event upstream of TCR complex amplification.","evidence":"Co-immunoprecipitation with kinase-dead Fyn mutant, phosphorylation assays","pmids":["21513984"],"confidence":"Medium","gaps":["No independent confirmation of Fyn as the sole relevant kinase","Structural basis of Fyn–TIM-1 association not determined"]},{"year":2013,"claim":"Demonstration that TIM-1 mediates broad enveloped-virus entry via PS on viral envelopes (apoptotic mimicry), with PS-binding-pocket mutants abolishing entry, generalized TIM-1 from an HAV-specific receptor to a pan-enveloped-virus attachment factor.","evidence":"Pseudovirion transduction with PS-pocket mutagenesis, PS liposome competition, annexin V substitution, multiple virus panels","pmids":["23698310"],"confidence":"High","gaps":["Whether TIM-1-mediated entry is sufficient or requires coreceptors for specific viruses","Post-attachment trafficking steps not defined"]},{"year":2014,"claim":"Identifying TIM-1 as a P-selectin ligand that mediates Th1/Th17 tethering and rolling in inflamed venules established a trafficking function for the mucin domain distinct from the IgV PS-binding role.","evidence":"Direct binding assays, intravital microscopy, mucin-domain-deleted knock-in mice, EAE and skin hypersensitivity models","pmids":["24703780"],"confidence":"High","gaps":["Glycan structures on TIM-1 mucin domain required for P-selectin binding not characterized","Relative contribution of TIM-1 versus PSGL-1 in T cell homing unclear"]},{"year":2015,"claim":"Three contemporaneous studies resolved downstream events: (1) TIM-1/p85 association recruits autophagy machinery (ATG5, ULK1) for phagosome maturation and tolerogenic antigen presentation; (2) TIM-1 in Bregs is required for AC-induced IL-10 and transplant tolerance; (3) TIM-1 interacts with NPC1 in endosomes for filovirus membrane fusion; and (4) TIM-1 also binds PE on viral envelopes, broadening its lipid recognition.","evidence":"Co-IP of KIM-1/p85, ATG5/ULK1 KO, T cell suppression assays; TIM-1Δmucin knock-in mice with allograft model and adoptive transfer rescue; TIM-1–NPC1 Co-IP and mAb-blocking of fusion; PE binding assays with Duramycin competition","pmids":["26282792","25645598","25855742","26575624","26487564"],"confidence":"High","gaps":["How TIM-1–NPC1 interaction is regulated in endosomes","Whether PE and PS compete for the same binding pocket or have overlapping sites","Whether autophagy-linked phagocytosis is the dominant clearance pathway in vivo"]},{"year":2018,"claim":"Mapping TIM-1 ubiquitination to specific cytoplasmic lysines and identifying STAM-1 (ESCRT-0) as a required partner for clathrin-mediated endocytosis defined the post-attachment trafficking mechanism for virus (DENV) internalization.","evidence":"CRISPR KO, TIRF live-cell microscopy, lysine mutagenesis, STAM-1 Co-IP, siRNA knockdown in Huh-7 cells","pmids":["29742433"],"confidence":"High","gaps":["E3 ubiquitin ligase responsible for TIM-1 ubiquitination not identified","Whether ubiquitination-dependent endocytosis applies to all TIM-1-mediated virus entries"]},{"year":2020,"claim":"Showing that both HAVCR1 and NPC1 are required for membrane fusion and cytoplasmic RNA delivery from exosome-associated HAV demonstrated that the TIM-1–NPC1 endosomal pathway operates for non-enveloped viruses exploiting exosome mimicry.","evidence":"CRISPR KO of HAVCR1 and NPC1, membrane fusion assay, RNA delivery assay","pmids":["32541946"],"confidence":"High","gaps":["Molecular mechanism linking NPC1 cholesterol transport function to TIM-1-mediated fusion unknown","Whether this pathway extends to non-viral exosome cargo delivery in physiology"]},{"year":2022,"claim":"CRISPR deletion of TIM-1 in human regulatory B cells revealed STAT3 as a downstream effector of TIM-1 signaling in Bregs, with TIM-1 required for suppressive function that is only partially IL-10-dependent.","evidence":"CRISPR KO in expanded human Bregs, STAT3 signaling assay, T cell suppression assay, humanized mouse skin transplant","pmids":["35660734"],"confidence":"Medium","gaps":["How TIM-1 activates STAT3 in B cells (intermediary kinase unknown)","Whether TIM-1-dependent Breg function operates through the same PI3K/p85 pathway as phagocytic cells"]},{"year":null,"claim":"Key unresolved questions include the identity of the E3 ligase ubiquitinating TIM-1, the structural basis for the TIM-1–NPC1 interaction in endosomes, whether TIM-1 PS/PE recognition is functionally separable in vivo, and how TIM-1 signaling differs mechanistically between T cells, B cells, and epithelial cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["E3 ligase for TIM-1 ubiquitination not identified","No high-resolution structure of TIM-1–NPC1 complex","In vivo contribution of PE versus PS binding not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,4,10,19,25]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3,18]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,4,9,19]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11,13,17,26]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11,13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,7,15,21,29,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,15,20,26]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,26]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,16,19,24]}],"complexes":[],"partners":["NPC1","FYN","STAM1","PIK3R1","ZAP70","ITK","SELP","CD300B"],"other_free_text":[]},"mechanistic_narrative":"HAVCR1 (TIM-1/KIM-1) is a type I transmembrane mucin-like glycoprotein that functions as a phosphatidylserine (PS) and phosphatidylethanolamine (PE) receptor, coupling apoptotic cell recognition and clearance to immune regulation and serving as a broad-spectrum entry receptor for enveloped viruses via apoptotic mimicry. Its IgV domain contains a PS/PE-binding cavity essential for phagocytosis of apoptotic cells, uptake of diverse enveloped viruses (filoviruses, flaviviruses, arenaviruses, alphaviruses), and regulatory B cell IL-10 production; it also directly binds Ebola virus glycoprotein at a site distinct from the PS pocket and cooperates with NPC1 in endosomes to enable membrane fusion during viral and exosomal cargo delivery [PMID:18082433, PMID:23698310, PMID:26575624, PMID:26487564, PMID:25855742, PMID:32541946]. On T cells, HAVCR1 associates with the CD3/TCR complex, amplifies Zap70/ITK/PI3K signaling and NF-AT-dependent transcription upon costimulation, functions as a P-selectin ligand via its mucin domain to mediate Th1/Th17 trafficking to inflamed tissues, and in B cells drives STAT3-dependent regulatory function and antibody production [PMID:17371991, PMID:19155484, PMID:24703780, PMID:25645598, PMID:35660734]. Its cytoplasmic tail undergoes Fyn kinase-dependent tyrosine phosphorylation and ubiquitination at specific lysine residues, which drives clathrin/ESCRT (STAM-1)-dependent endocytosis and recruits PI3K/p85, coupling receptor internalization to autophagy-related phagosome maturation and pro-tolerogenic antigen presentation [PMID:21513984, PMID:29742433, PMID:26282792]."},"prefetch_data":{"uniprot":{"accession":"Q96D42","full_name":"Hepatitis A virus cellular receptor 1","aliases":["Kidney injury molecule 1","KIM-1","T-cell immunoglobulin and mucin domain-containing protein 1","TIMD-1","T-cell immunoglobulin mucin receptor 1","TIM","TIM-1","T-cell membrane protein 1"],"length_aa":364,"mass_kda":39.2,"function":"Phosphatidylserine receptor that plays an important functional role in regulatory B-cell homeostasis including generation, expansion and suppressor functions (By similarity). As P-selectin/SELPLG ligand, plays a specialized role in activated but not naive T-cell trafficking during inflammatory responses (PubMed:24703780). Controls thereby T-cell accumulation in the inflamed central nervous system (CNS) and the induction of autoimmune disease (PubMed:24703780). Also regulates expression of various anti-inflammatory cytokines and co-inhibitory ligands including IL10 (By similarity). Acts as a regulator of T-cell proliferation (By similarity). Confers phagocytic ability on injured kidney epithelial cells, allowing them to bind to and internalize apoptotic bodies and necrotic debris following kidney injury (PubMed:18414680). The ectodomain binds to the surface of apoptotic kidney epithelial cells via phosphatidylserine and oxidized phospholipids exposed on the cell membrane of the apoptotic cells (PubMed:18414680). HAVCR1-expressing cells are also capable of phagocytosing Gram-negative and Gram-positive bacteria (PubMed:18414680) (Microbial infection) Acts as a receptor for Hepatitis A virus (Microbial infection) Acts as a receptor for Ebolavirus and Marburg virus by binding exposed phosphatidyl-serine at the surface of virion membrane (PubMed:21536871). Serves as a dual receptor for Ebolavirus by also interacting with envelope glycoprotein GP (PubMed:26487564) (Microbial infection) Acts as a receptor for Dengue virus by binding exposed phosphatidyl-serine at the surface of virion membrane (PubMed:23084921). TIM1 and Dengue virus are co-internalized during virus entry (PubMed:29742433) (Microbial infection) Acts as a receptor for Zika virus by binding to envelope protein E (Microbial infection) Plays a positive role in Chikungunya virus cell entry","subcellular_location":"Cell membrane; Cell projection, phagocytic cup; Cytoplasmic vesicle, phagosome","url":"https://www.uniprot.org/uniprotkb/Q96D42/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HAVCR1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HAVCR1","total_profiled":1310},"omim":[{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"},{"mim_id":"610705","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER B; CD300LB","url":"https://www.omim.org/entry/610705"},{"mim_id":"610096","title":"T-CELL IMMUNOGLOBULIN AND MUCIN DOMAINS-CONTAINING PROTEIN 4; TIMD4","url":"https://www.omim.org/entry/610096"},{"mim_id":"606652","title":"HEPATITIS A VIRUS CELLULAR RECEPTOR 2; HAVCR2","url":"https://www.omim.org/entry/606652"},{"mim_id":"606518","title":"HEPATITIS A VIRUS CELLULAR RECEPTOR 1; HAVCR1","url":"https://www.omim.org/entry/606518"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":4.3},{"tissue":"kidney","ntpm":6.5}],"url":"https://www.proteinatlas.org/search/HAVCR1"},"hgnc":{"alias_symbol":["HAVCR-1","TIM-1","TIM1","HAVCR","TIMD1","CD365","KIM1"],"prev_symbol":[]},"alphafold":{"accession":"Q96D42","domains":[{"cath_id":"2.60.40.10","chopping":"20-126","consensus_level":"high","plddt":92.8892,"start":20,"end":126}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96D42","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96D42-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96D42-F1-predicted_aligned_error_v6.png","plddt_mean":65.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HAVCR1","jax_strain_url":"https://www.jax.org/strain/search?query=HAVCR1"},"sequence":{"accession":"Q96D42","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96D42.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96D42/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96D42"}},"corpus_meta":[{"pmid":"18082433","id":"PMC_18082433","title":"TIM-1 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tumor progression and patient outcome.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24390735","citation_count":73,"is_preprint":false},{"pmid":"21339644","id":"PMC_21339644","title":"A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans.","date":"2011","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/21339644","citation_count":70,"is_preprint":false},{"pmid":"25855742","id":"PMC_25855742","title":"Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25855742","citation_count":66,"is_preprint":false},{"pmid":"28874468","id":"PMC_28874468","title":"TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A 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experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution in receptor-negative cells with direct virus binding and infection readout\",\n      \"pmids\": [\"9658108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIM-1 (HAVCR1) specifically binds phosphatidylserine (PS) on the surface of apoptotic cells (but not other phospholipids), and TIM-1-expressing cells efficiently phagocytose apoptotic cells; mutations in the unique IgV cavity of TIM-1 eliminated PS binding and phagocytosis.\",\n      \"method\": \"Phospholipid binding assay, phagocytosis assay with transfected cells and primary kidney cells, MAb blocking, site-directed mutagenesis of PS-binding cavity\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding reconstitution, mutagenesis, and functional phagocytosis assay in multiple cell types\",\n      \"pmids\": [\"18082433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIM-1 functions as a T cell costimulatory molecule expressed on activated CD4+ T cells; TIM-1-specific MAb ligation plus TCR stimulation enhanced T cell proliferation and IL-4 production preferentially in Th2 cells; in vivo TIM-1 ligation prevented respiratory tolerance.\",\n      \"method\": \"Anti-TIM-1 mAb stimulation of purified CD4+ T cells in vitro, cytokine ELISA, in vivo antigen + anti-TIM-1 treatment with pulmonary inflammation readout\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro costimulation, in vivo tolerance model) with specific functional readouts\",\n      \"pmids\": [\"15793575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human TIM-1 associates with the TCR-signaling complex via CD3, upregulates phosphorylation of Zap70 and ITK, requires TIM-1 tyrosine phosphorylation for this activity, and induces formation of a novel complex including PI3K and ITK, leading to increased effector cytokine expression.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, complex formation analysis in T cells, cytokine production assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mechanistic follow-up (phosphorylation, complex formation, tyrosine requirement), multiple methods\",\n      \"pmids\": [\"17371991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TIM-1 mediates enveloped virus entry via apoptotic mimicry: key PS-binding residues in the IgV domain are critical for Ebola virus (EBOV) entry through direct interaction with PS on the viral envelope; PS liposomes competed with TIM-1 for EBOV pseudovirion binding; TIM-1 enhanced infection of a broad range of enveloped viruses including alphaviruses, and mediated glycoprotein-independent virus uptake.\",\n      \"method\": \"Pseudovirion transduction assay, PS liposome competition, site-directed mutagenesis of PS-binding pocket, annexin V substitution experiments, virus-like particle uptake assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of active site plus multiple functional assays and competition experiments\",\n      \"pmids\": [\"23698310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIM-1 is an endogenous ligand for the activating myeloid receptor LMIR5/CD300b; the Ig-like domain of LMIR5 binds TIM-1 near its PS-binding site; TIM-1 stimulation activates mast cells via LMIR5; TIM-1–LMIR5 interaction promotes neutrophil recruitment in vivo.\",\n      \"method\": \"Retrovirus-mediated expression cloning, protein binding assays, mast cell activation assay, in vivo neutrophil recruitment model, LMIR5 knockout mice\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — expression cloning identification, binding domain mapping, and in vivo functional validation with knockout mice\",\n      \"pmids\": [\"20566714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIM-1/TIM-1-mediated phagocytosis of apoptotic cells requires KIM-1 phosphorylation and association with p85 (PI3K regulatory subunit), leading to LC3 lipidation and phagosome encapsulation; autophagy genes (ATG5, ULK1) are required for efficient apoptotic cell clearance and phagosome maturation; KIM-1-mediated phagocytosis promotes pro-tolerogenic antigen presentation that suppresses CD4 T-cell proliferation and increases regulatory T cells.\",\n      \"method\": \"Co-immunoprecipitation (KIM-1/p85), LC3 lipidation assay, ROS measurement, NOX inhibition, autophagy gene KO, antigen presentation assay, T cell proliferation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including Co-IP, genetic KO of autophagy genes, and functional immune readouts\",\n      \"pmids\": [\"26282792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIM-1 signaling in regulatory B cells (Bregs) is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production; TIM-1 mucin domain mutant mice (TIM-1Δmucin) show decreased PS binding and fail to produce IL-10 in response to ACs or TIM-1 ligation, and exhibit accelerated allograft rejection; transfer of WT TIM-1+ B cells restores graft survival.\",\n      \"method\": \"Loss-of-function mucin-domain mutant knock-in mice, apoptotic cell binding assay, IL-10 production assay, allograft rejection model, B cell adoptive transfer\",\n      \"journal\": \"American journal of transplantation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific knock-in mutant with multiple functional readouts and rescue by adoptive transfer\",\n      \"pmids\": [\"25645598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IgA is a natural ligand of HAVCR1/TIM-1; IgA binds specifically to TIM-1 via the IgV domain; the IgA and HAV binding sites on HAVCR1 are distinct epitopes; IgA association with HAVCR1 synergistically enhances HAV neutralization by HAVCR1-Fc fusion protein.\",\n      \"method\": \"Expression cloning of cDNA library with HAVCR1-Fc fusion protein, ELISA binding assay, MAb blocking, HAV neutralization assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — expression cloning plus binding and functional neutralization assays from single study\",\n      \"pmids\": [\"17229699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIM-1 glycoprotein is a P-selectin ligand; the TIM-1 mucin domain mediates tethering and rolling of Th1 and Th17 cells on P-selectin, and the IgV domain is also required for P-selectin binding; Th1/Th17 cells lacking TIM-1 mucin domain show reduced rolling in inflamed venules; TIM-1 blockade reduces T cell recruitment in skin hypersensitivity and blocks EAE.\",\n      \"method\": \"Binding assay (human and murine TIM-1 to P-selectin), intravital microscopy of mesenteric venules and brain microcirculation, mucin-domain-deleted mutant mice, skin hypersensitivity and EAE models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay, domain-deletion mutant, intravital microscopy, and multiple in vivo disease models\",\n      \"pmids\": [\"24703780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Phosphatidylethanolamine (PE) is a ligand for TIM-1; TIM-1 efficiently binds PE present on viral envelopes (West Nile, dengue, Ebola virions); PE on apoptotic cells promotes phagocytic uptake by TIM-1-expressing cells; the PE-binding cyclic peptide Duramycin blocks TIM-1-mediated (but not L-SIGN-mediated) virus entry by blocking virus attachment to TIM-1.\",\n      \"method\": \"Phospholipid binding assay, pseudovirus infection assay, Duramycin competition assay, phagocytosis assay, apoptotic cell PE exposure measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding, specific inhibition with PE-blocking compound, and multiple virus entry assays\",\n      \"pmids\": [\"26575624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIM-1 and NPC1 colocalize and physically interact in intracellular vesicles where EBOV glycoprotein-mediated membrane fusion occurs; a TIM-1-specific mAb (M224/1) blocked GP-mediated fusion and interfered with TIM-1–NPC1 binding, demonstrating that the TIM-1–NPC1 interaction is required for filovirus membrane fusion.\",\n      \"method\": \"Co-localization (immunofluorescence), Co-immunoprecipitation/binding assay, mAb blocking of fusion and protein–protein interaction, pseudovirus infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional blockade with mechanistic antibody, replicated across multiple filovirus species\",\n      \"pmids\": [\"25855742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIM-1 directly interacts with EBOV glycoprotein (GP) in addition to binding PS on the viral envelope; crystal structures of hTIM-1 and hTIM-4 IgV domains were determined; chimeric and point-mutant analyses mapped the GP-binding region on hTIM-1 distinct from the PS-binding site.\",\n      \"method\": \"In vitro direct binding assay (TIM-1/EBOV GP), X-ray crystallography, chimeric protein construction, site-directed mutagenesis, pseudovirion infection assay\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro binding, mutagenesis, and functional infection assay\",\n      \"pmids\": [\"26487564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TIM-1 is an authentic DENV entry receptor that is co-internalized with DENV in clathrin-coated pits; TIM-1 is ubiquitinated at two cytoplasmic lysine residues, and this ubiquitination is required for DENV endocytosis; STAM-1 (ESCRT-0 component) interacts with TIM-1 and is required for DENV infection.\",\n      \"method\": \"CRISPR/Cas9 TIM-1 KO, TIRF live-cell microscopy, ubiquitination assay, lysine mutagenesis, STAM-1 Co-IP, siRNA knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO, live imaging, ubiquitination site mapping by mutagenesis, and Co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"29742433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fyn kinase (Src family) physically associates with TIM-1 and is required for phosphorylation of the conserved tyrosine in the TIM-1 cytoplasmic tail; Fyn–TIM-1 association does not require Fyn kinase activity; TIM-1 tyrosine phosphorylation level varies with Fyn expression.\",\n      \"method\": \"Co-immunoprecipitation, kinase-dead Fyn mutant, phosphorylation assay, Fyn expression modulation\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with mechanistic follow-up (kinase-dead mutant, phosphorylation assay), single lab\",\n      \"pmids\": [\"21513984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TIM-1 ligation induces polyclonal T cell activation independently of conventional TCR signal 1, requiring strong costimulation from mature dendritic cells; TIM-1 stimulation raises free cytosolic calcium, triggers calcineurin-dependent NF-AT nuclear translocation, and induces IL-2 transcription; TIM-4 on mature DCs serves as the TIM-1 counter-receptor.\",\n      \"method\": \"Anti-TIM-1 mAb stimulation in vitro, calcium flux assay, NF-AT translocation assay, IL-2 reporter, calcineurin inhibitor\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts (Ca2+, NF-AT, IL-2) with pharmacologic inhibition, single lab\",\n      \"pmids\": [\"19155484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EBOV directly binds primary T lymphocytes in a phosphatidylserine–TIM-1-dependent manner (without detectable viral replication), causing rapid non-antigen-specific T cell activation, cytokine production, and a cytokine storm-like phenomenon; TIM-1 knockout mice show increased survival and reduced inflammatory response after EBOV challenge with only modest reduction in viremia.\",\n      \"method\": \"TIM-1 KO mice EBOV challenge, in vitro EBOV binding assay with primary T cells, flow cytometry (CD4Hi CD3Low population), cytokine/chemokine measurement, transcriptome analysis, Western blot\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice plus multiple in vitro mechanistic assays (binding, activation, transcriptomics), orthogonal methods\",\n      \"pmids\": [\"28951472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HAVCR1 and NPC1 both participate in clathrin-mediated endocytosis and membrane fusion of exosome-associated HAV (exo-HAV); CRISPR-Cas9 knockout of either HAVCR1 or NPC1 blocks membrane fusion and cytoplasmic RNA delivery from exo-HAV; the HAVCR1–NPC1 pathway mediates HAV infection via exosome mimicry without requiring an envelope glycoprotein.\",\n      \"method\": \"CRISPR/Cas9 knockout of HAVCR1 and NPC1, membrane fusion assay, RNA delivery assay, methylene blue inactivation of non-encapsidated RNA\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR KO with direct functional assays for fusion and RNA delivery, two receptor KOs tested\",\n      \"pmids\": [\"32541946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HAVCR1 and its mouse ortholog are functional HAV receptors: CRISPR/Cas9 knockout of monkey HAVCR1 in AGMK cells abolishes susceptibility to both naked HAV and exo-HAV infection; transfection of HAVCR1 or mouse mHavcr1 cDNA into KO cells restores susceptibility.\",\n      \"method\": \"CRISPR/Cas9 KO, cDNA rescue (HAVCR1 and mHavcr1 transfection), HAV infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — genetic KO with full rescue by receptor cDNA, definitive functional reconstitution\",\n      \"pmids\": [\"29437974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIM-1 promotes HCV infection by serving as an attachment receptor that binds PS exposed on the HCV envelope; TIM-1 KO in Huh-7.5 cells reduces HCV cell attachment and infection; ectopic TIM-1 (but not TIM-3 or TIM-4) rescues infection; PS liposomes block HCV attachment and infection; HCV particles could be immunoprecipitated with PS-specific antibody.\",\n      \"method\": \"CRISPR/Cas9 TIM-1 KO, ectopic expression rescue, PS liposome competition, anti-PS immunoprecipitation of HCV particles, siRNA knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with specific rescue, competition assay, and immunoprecipitation of virus–PS complex\",\n      \"pmids\": [\"27807228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HAVCR1/KIM-1 activates the IL-6/STAT-3/HIF-1A signaling axis in clear cell renal cell carcinoma; this activation depends on HAVCR1 ectodomain shedding, as determined by microarray analysis of cells with upregulated or silenced HAVCR1.\",\n      \"method\": \"HAVCR1 overexpression and siRNA silencing, microarray, STAT-3 phosphorylation assay, HIF-1A measurement, ectodomain shedding assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with signaling pathway readout, single lab\",\n      \"pmids\": [\"24390735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIM-1 signaling in dendritic cells upregulates costimulatory molecule expression and proinflammatory cytokine production, promoting effector T cell responses while inhibiting Foxp3+ Treg responses; high-avidity anti-TIM-1 antibody enhances DC immunogenic function and promotes Th17 responses in vivo.\",\n      \"method\": \"Anti-TIM-1 mAb stimulation of DCs, flow cytometry (costimulatory molecules), cytokine measurement, in vivo EAE model with high- vs. low-avidity antibodies\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro DC activation plus in vivo disease model, single lab\",\n      \"pmids\": [\"21469101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HAV interaction with soluble HAVCR1 requires calcium (not replaceable by Li, Na, Mg, Mn, or Zn), is temperature-dependent (faster at 37°C than 4°C), and occurs at pH 5–8 (most efficient pH 6–7); soluble HAVCR1 neutralizes wild-type HAV, confirming the receptor's role in authentic virus entry.\",\n      \"method\": \"Soluble receptor neutralization and alteration assays, ion substitution experiments, temperature and pH variation, wt HAV cell culture system\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical characterization of receptor–virus interaction with multiple conditions tested\",\n      \"pmids\": [\"19860892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIM-1 is expressed on mast cells and its ligation by TIM-4 (its ligand on DCs) promotes IL-4, IL-6, and IL-13 production without enhancing degranulation in IgE+Ag-stimulated mast cells.\",\n      \"method\": \"Flow cytometry (TIM-1/TIM-3 expression on mast cells), recombinant TIM-4 stimulation of bone marrow-derived mast cells, cytokine ELISA, degranulation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ligand stimulation with specific cytokine and degranulation readouts\",\n      \"pmids\": [\"17620455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIM-1/TIM-1 is a receptor for SARS-CoV-2 in lung and kidney epithelial cells; KIM-1-expressing cells that lack ACE2 are permissive to SARS-CoV-2 infection; KIM-1 binds the SARS-CoV-2 Spike protein in vitro; anti-KIM-1 antibodies and TW-37 inhibit KIM-1-mediated uptake of Spike-displaying virosomes.\",\n      \"method\": \"In vitro Spike protein binding assay, nanoparticle/virosome uptake assay, anti-KIM-1 antibody blocking, SARS-CoV-2 infection of KIM-1-expressing/ACE2-negative cells, TW-37 inhibition\",\n      \"journal\": \"medRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding plus functional infection with ACE2-negative cells, preprint\",\n      \"pmids\": [\"32995803\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TIM-1 mediates dystroglycan-independent entry of Lassa virus (LASV) pseudovirions through interaction of virion-associated PtdSer with the IgV PtdSer-binding pocket of TIM-1; mutagenesis of PS-binding pocket abrogates transduction; chimeric TIM-1 lacking the mucin domain but retaining the IgV domain is competent as a receptor.\",\n      \"method\": \"CRISPR/Cas9 αDG knockout, pseudovirus transduction assay, IgV domain mutagenesis, mAb ARD5 blocking assay, chimeric TIM-1 rescue\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of functional domain with specific rescue, multiple conditions tested\",\n      \"pmids\": [\"29875238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIM-1 promotes DENV-induced autophagy as a signaling receptor: TIM-1 colocalizes with autophagosomes during DENV infection (co-transported with virus); TIM-1 knockdown reduces both DENV internalization and autophagy activation; TIM-1-mediated autophagy requires p85 (PI3K subunit), which co-localizes with TIM-1 at Rab5-positive endosomes.\",\n      \"method\": \"Confocal microscopy (TIM-1/autophagosome co-localization), siRNA knockdown of TIM-1 and p85, GFP-LC3 autophagy reporter, co-localization at Rab5 endosomes\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-localization plus siRNA knockdown with mechanistic pathway (PI3K/p85) identification\",\n      \"pmids\": [\"31581681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Semaphorin 4A (Sema4A) and H-ferritin utilize TIM-1 on human oligodendrocytes: TIM-1 mediates Sema4A-induced apoptosis and H-ferritin uptake (iron delivery) in human oligodendrocytes; H-ferritin can block Sema4A-mediated cytotoxicity via TIM-1.\",\n      \"method\": \"TIM-1 expression in human oligodendrocytes, Sema4A apoptosis assay, H-ferritin uptake assay, TIM-1 blocking experiments\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct receptor identification with functional apoptosis and iron uptake readouts, single lab\",\n      \"pmids\": [\"29457657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Epsilon toxin from Clostridium perfringens binds HAVCR1 as a cell surface receptor; aromatic amino acids Y29, Y30, Y36, and Y196 in the toxin are critical for binding to HAVCR1 and host cells; mutant toxins (e.g., Etx-Y29E) are defective in HAVCR1 binding, cell binding, and cytotoxic activity.\",\n      \"method\": \"Site-directed mutagenesis of epsilon toxin, cell binding assay, HAVCR1 binding assay, cytotoxicity assay, circular dichroism spectroscopy\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of toxin binding determinants with functional cell and receptor binding readouts\",\n      \"pmids\": [\"22938730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation into plasma cells; anti-TIM-1 mAb stimulation of activated B cells increased IgG2b and IgG3 secretion in vitro; in vivo TIM-1 ligation increased OVA-specific IgG2b, IgG3, and IgE in immunized mice.\",\n      \"method\": \"Anti-TIM-1 mAb stimulation of activated B cells, proliferation assay, syndecan-1 (CD138) expression, antibody ELISA, in vivo immunization with T-dependent and T-independent antigens\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"21303660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIM-1 regulates STAT3 signaling in regulatory B cells and modulates their suppressive function; CRISPR-mediated TIM-1 deletion demonstrates predominant roles for TIM-1 (and CD154) in expBreg-mediated suppressive function that is only partially IL-10-dependent.\",\n      \"method\": \"CRISPR-mediated gene deletion in human expanded B cells, STAT3 signaling assay, T cell suppression assay, humanized mouse skin transplant model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with signaling pathway readout and in vivo transplant model, single lab\",\n      \"pmids\": [\"35660734\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HAVCR1/TIM-1 is a type I transmembrane mucin-like glycoprotein that acts as a phosphatidylserine (and phosphatidylethanolamine) receptor mediating phagocytosis of apoptotic cells, broad enveloped-virus entry via apoptotic mimicry, and T/B cell costimulation: its IgV domain PS-binding cavity is required for apoptotic cell clearance, filovirus/flavivirus/arenavirus entry, and regulatory B cell IL-10 production; its cytoplasmic tail undergoes Fyn-dependent tyrosine phosphorylation and ubiquitination that drives clathrin/ESCRT-dependent endocytosis; it associates with CD3/TCR complex to amplify Zap70/ITK/PI3K signaling in T cells; it binds P-selectin via its mucin domain to mediate Th1/Th17 trafficking; and it interacts with NPC1 in endosomes to enable membrane fusion during viral and exosomal cargo delivery.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HAVCR1 (TIM-1/KIM-1) is a type I transmembrane mucin-like glycoprotein that functions as a phosphatidylserine (PS) and phosphatidylethanolamine (PE) receptor, coupling apoptotic cell recognition and clearance to immune regulation and serving as a broad-spectrum entry receptor for enveloped viruses via apoptotic mimicry. Its IgV domain contains a PS/PE-binding cavity essential for phagocytosis of apoptotic cells, uptake of diverse enveloped viruses (filoviruses, flaviviruses, arenaviruses, alphaviruses), and regulatory B cell IL-10 production; it also directly binds Ebola virus glycoprotein at a site distinct from the PS pocket and cooperates with NPC1 in endosomes to enable membrane fusion during viral and exosomal cargo delivery [PMID:18082433, PMID:23698310, PMID:26575624, PMID:26487564, PMID:25855742, PMID:32541946]. On T cells, HAVCR1 associates with the CD3/TCR complex, amplifies Zap70/ITK/PI3K signaling and NF-AT-dependent transcription upon costimulation, functions as a P-selectin ligand via its mucin domain to mediate Th1/Th17 trafficking to inflamed tissues, and in B cells drives STAT3-dependent regulatory function and antibody production [PMID:17371991, PMID:19155484, PMID:24703780, PMID:25645598, PMID:35660734]. Its cytoplasmic tail undergoes Fyn kinase-dependent tyrosine phosphorylation and ubiquitination at specific lysine residues, which drives clathrin/ESCRT (STAM-1)-dependent endocytosis and recruits PI3K/p85, coupling receptor internalization to autophagy-related phagosome maturation and pro-tolerogenic antigen presentation [PMID:21513984, PMID:29742433, PMID:26282792].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of HAVCR1 as the functional cellular receptor for hepatitis A virus established the gene as a virus entry factor and defined its basic topology as a type I integral-membrane mucin-like glycoprotein.\",\n      \"evidence\": \"cDNA transfection into receptor-negative dog cells conferring HAV binding and infection\",\n      \"pmids\": [\"9658108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of HAV internalization unknown\", \"No knowledge of non-viral ligands or immune function\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that TIM-1 ligation costimulates T cell activation and Th2 cytokine production revealed a second, immune-regulatory role beyond virus entry.\",\n      \"evidence\": \"Anti-TIM-1 mAb costimulation of purified CD4+ T cells plus in vivo tolerance model\",\n      \"pmids\": [\"15793575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of TIM-1 in T cells unknown\", \"Natural ligand for costimulatory function not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that TIM-1 binds phosphatidylserine through a unique IgV cavity and mediates phagocytosis of apoptotic cells unified its viral and immune functions under a single PS-recognition mechanism.\",\n      \"evidence\": \"Phospholipid binding assays, site-directed mutagenesis of PS-binding cavity, phagocytosis reconstitution in transfected and primary kidney cells\",\n      \"pmids\": [\"18082433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PS binding accounts for all viral entry or additional receptor–ligand contacts exist\", \"Downstream signaling from PS engagement uncharacterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping TIM-1 association with the CD3/TCR complex and identification of Zap70/ITK/PI3K phosphorylation cascade explained how TIM-1 amplifies T cell activation at a molecular level.\",\n      \"evidence\": \"Co-immunoprecipitation of TIM-1 with CD3, phosphorylation assays for Zap70 and ITK, tyrosine-mutant analysis\",\n      \"pmids\": [\"17371991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase phosphorylating TIM-1 cytoplasmic tail unknown\", \"Structural basis of TIM-1–CD3 association not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that TIM-1 ligation induces calcium flux, NF-AT nuclear translocation, and IL-2 transcription linked TIM-1 to the canonical calcineurin/NF-AT pathway, and identified TIM-4 on DCs as a counter-receptor.\",\n      \"evidence\": \"Calcium flux assay, NF-AT translocation, calcineurin inhibitor blockade, IL-2 reporter in stimulated T cells\",\n      \"pmids\": [\"19155484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TIM-4 is the sole physiological ligand for costimulation\", \"Relative contribution of PS-binding versus protein–protein interaction with TIM-4 unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of Fyn kinase as the Src-family kinase that physically associates with and phosphorylates the TIM-1 cytoplasmic tyrosine resolved the proximal signaling event upstream of TCR complex amplification.\",\n      \"evidence\": \"Co-immunoprecipitation with kinase-dead Fyn mutant, phosphorylation assays\",\n      \"pmids\": [\"21513984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent confirmation of Fyn as the sole relevant kinase\", \"Structural basis of Fyn–TIM-1 association not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that TIM-1 mediates broad enveloped-virus entry via PS on viral envelopes (apoptotic mimicry), with PS-binding-pocket mutants abolishing entry, generalized TIM-1 from an HAV-specific receptor to a pan-enveloped-virus attachment factor.\",\n      \"evidence\": \"Pseudovirion transduction with PS-pocket mutagenesis, PS liposome competition, annexin V substitution, multiple virus panels\",\n      \"pmids\": [\"23698310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TIM-1-mediated entry is sufficient or requires coreceptors for specific viruses\", \"Post-attachment trafficking steps not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying TIM-1 as a P-selectin ligand that mediates Th1/Th17 tethering and rolling in inflamed venules established a trafficking function for the mucin domain distinct from the IgV PS-binding role.\",\n      \"evidence\": \"Direct binding assays, intravital microscopy, mucin-domain-deleted knock-in mice, EAE and skin hypersensitivity models\",\n      \"pmids\": [\"24703780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan structures on TIM-1 mucin domain required for P-selectin binding not characterized\", \"Relative contribution of TIM-1 versus PSGL-1 in T cell homing unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Three contemporaneous studies resolved downstream events: (1) TIM-1/p85 association recruits autophagy machinery (ATG5, ULK1) for phagosome maturation and tolerogenic antigen presentation; (2) TIM-1 in Bregs is required for AC-induced IL-10 and transplant tolerance; (3) TIM-1 interacts with NPC1 in endosomes for filovirus membrane fusion; and (4) TIM-1 also binds PE on viral envelopes, broadening its lipid recognition.\",\n      \"evidence\": \"Co-IP of KIM-1/p85, ATG5/ULK1 KO, T cell suppression assays; TIM-1Δmucin knock-in mice with allograft model and adoptive transfer rescue; TIM-1–NPC1 Co-IP and mAb-blocking of fusion; PE binding assays with Duramycin competition\",\n      \"pmids\": [\"26282792\", \"25645598\", \"25855742\", \"26575624\", \"26487564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TIM-1–NPC1 interaction is regulated in endosomes\", \"Whether PE and PS compete for the same binding pocket or have overlapping sites\", \"Whether autophagy-linked phagocytosis is the dominant clearance pathway in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapping TIM-1 ubiquitination to specific cytoplasmic lysines and identifying STAM-1 (ESCRT-0) as a required partner for clathrin-mediated endocytosis defined the post-attachment trafficking mechanism for virus (DENV) internalization.\",\n      \"evidence\": \"CRISPR KO, TIRF live-cell microscopy, lysine mutagenesis, STAM-1 Co-IP, siRNA knockdown in Huh-7 cells\",\n      \"pmids\": [\"29742433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase responsible for TIM-1 ubiquitination not identified\", \"Whether ubiquitination-dependent endocytosis applies to all TIM-1-mediated virus entries\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that both HAVCR1 and NPC1 are required for membrane fusion and cytoplasmic RNA delivery from exosome-associated HAV demonstrated that the TIM-1–NPC1 endosomal pathway operates for non-enveloped viruses exploiting exosome mimicry.\",\n      \"evidence\": \"CRISPR KO of HAVCR1 and NPC1, membrane fusion assay, RNA delivery assay\",\n      \"pmids\": [\"32541946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking NPC1 cholesterol transport function to TIM-1-mediated fusion unknown\", \"Whether this pathway extends to non-viral exosome cargo delivery in physiology\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR deletion of TIM-1 in human regulatory B cells revealed STAT3 as a downstream effector of TIM-1 signaling in Bregs, with TIM-1 required for suppressive function that is only partially IL-10-dependent.\",\n      \"evidence\": \"CRISPR KO in expanded human Bregs, STAT3 signaling assay, T cell suppression assay, humanized mouse skin transplant\",\n      \"pmids\": [\"35660734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TIM-1 activates STAT3 in B cells (intermediary kinase unknown)\", \"Whether TIM-1-dependent Breg function operates through the same PI3K/p85 pathway as phagocytic cells\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the E3 ligase ubiquitinating TIM-1, the structural basis for the TIM-1–NPC1 interaction in endosomes, whether TIM-1 PS/PE recognition is functionally separable in vivo, and how TIM-1 signaling differs mechanistically between T cells, B cells, and epithelial cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"E3 ligase for TIM-1 ubiquitination not identified\", \"No high-resolution structure of TIM-1–NPC1 complex\", \"In vivo contribution of PE versus PS binding not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 4, 10, 19, 25]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3, 18]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 4, 9, 19]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11, 13, 17, 26]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 7, 15, 21, 29, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 15, 20, 26]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 26]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 16, 19, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NPC1\",\n      \"FYN\",\n      \"STAM1\",\n      \"PIK3R1\",\n      \"ZAP70\",\n      \"ITK\",\n      \"SELP\",\n      \"CD300B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}