Affinage

HAVCR1

Hepatitis A virus cellular receptor 1 · UniProt Q96D42

Length
364 aa
Mass
39.2 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    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

    PMID:9658108

    Open questions at the time
    • Mechanism of HAV internalization unknown
    • No knowledge of non-viral ligands or immune function
  2. 2005 High

    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

    PMID:15793575

    Open questions at the time
    • Signaling pathway downstream of TIM-1 in T cells unknown
    • Natural ligand for costimulatory function not identified
  3. 2007 High

    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

    PMID:18082433

    Open questions at the time
    • Whether PS binding accounts for all viral entry or additional receptor–ligand contacts exist
    • Downstream signaling from PS engagement uncharacterized
  4. 2007 High

    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

    PMID:17371991

    Open questions at the time
    • Identity of the kinase phosphorylating TIM-1 cytoplasmic tail unknown
    • Structural basis of TIM-1–CD3 association not resolved
  5. 2009 Medium

    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

    PMID:19155484

    Open questions at the time
    • Whether TIM-4 is the sole physiological ligand for costimulation
    • Relative contribution of PS-binding versus protein–protein interaction with TIM-4 unclear
  6. 2011 Medium

    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

    PMID:21513984

    Open questions at the time
    • No independent confirmation of Fyn as the sole relevant kinase
    • Structural basis of Fyn–TIM-1 association not determined
  7. 2013 High

    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

    PMID:23698310

    Open questions at the time
    • Whether TIM-1-mediated entry is sufficient or requires coreceptors for specific viruses
    • Post-attachment trafficking steps not defined
  8. 2014 High

    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

    PMID:24703780

    Open questions at the time
    • 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
  9. 2015 High

    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

    PMID:25645598 PMID:25855742 PMID:26282792 PMID:26487564 PMID:26575624

    Open questions at the time
    • 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
  10. 2018 High

    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

    PMID:29742433

    Open questions at the time
    • E3 ubiquitin ligase responsible for TIM-1 ubiquitination not identified
    • Whether ubiquitination-dependent endocytosis applies to all TIM-1-mediated virus entries
  11. 2020 High

    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

    PMID:32541946

    Open questions at the time
    • 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
  12. 2022 Medium

    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

    PMID:35660734

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 5 GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 6 GO:0005768 endosome 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 2
Partners
CD300BFYNITKNPC1PIK3R1SELPSTAM1ZAP70

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. cDNA transfection into receptor-negative dog cells, HAV binding assay, infection susceptibility assay, MAb blocking experiments Journal of virology High 9658108
2007 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. Phospholipid binding assay, phagocytosis assay with transfected cells and primary kidney cells, MAb blocking, site-directed mutagenesis of PS-binding cavity Immunity High 18082433
2005 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. 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 Nature immunology High 15793575
2007 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. Co-immunoprecipitation, phosphorylation assays, complex formation analysis in T cells, cytokine production assay Journal of immunology High 17371991
2013 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. Pseudovirion transduction assay, PS liposome competition, site-directed mutagenesis of PS-binding pocket, annexin V substitution experiments, virus-like particle uptake assay Journal of virology High 23698310
2007 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. Retrovirus-mediated expression cloning, protein binding assays, mast cell activation assay, in vivo neutrophil recruitment model, LMIR5 knockout mice The Journal of experimental medicine High 20566714
2015 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. Co-immunoprecipitation (KIM-1/p85), LC3 lipidation assay, ROS measurement, NOX inhibition, autophagy gene KO, antigen presentation assay, T cell proliferation assay The EMBO journal High 26282792
2015 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. Loss-of-function mucin-domain mutant knock-in mice, apoptotic cell binding assay, IL-10 production assay, allograft rejection model, B cell adoptive transfer American journal of transplantation High 25645598
2009 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. Expression cloning of cDNA library with HAVCR1-Fc fusion protein, ELISA binding assay, MAb blocking, HAV neutralization assay Journal of virology Medium 17229699
2014 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. 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 Immunity High 24703780
2015 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. Phospholipid binding assay, pseudovirus infection assay, Duramycin competition assay, phagocytosis assay, apoptotic cell PE exposure measurement Proceedings of the National Academy of Sciences of the United States of America High 26575624
2015 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. Co-localization (immunofluorescence), Co-immunoprecipitation/binding assay, mAb blocking of fusion and protein–protein interaction, pseudovirus infection assay Journal of virology High 25855742
2015 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. In vitro direct binding assay (TIM-1/EBOV GP), X-ray crystallography, chimeric protein construction, site-directed mutagenesis, pseudovirion infection assay Protein & cell High 26487564
2018 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. CRISPR/Cas9 TIM-1 KO, TIRF live-cell microscopy, ubiquitination assay, lysine mutagenesis, STAM-1 Co-IP, siRNA knockdown Cell reports High 29742433
2011 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. Co-immunoprecipitation, kinase-dead Fyn mutant, phosphorylation assay, Fyn expression modulation Molecular immunology Medium 21513984
2009 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. Anti-TIM-1 mAb stimulation in vitro, calcium flux assay, NF-AT translocation assay, IL-2 reporter, calcineurin inhibitor Journal of immunology Medium 19155484
2017 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. 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 mBio High 28951472
2020 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. CRISPR/Cas9 knockout of HAVCR1 and NPC1, membrane fusion assay, RNA delivery assay, methylene blue inactivation of non-encapsidated RNA Nature microbiology High 32541946
2018 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. CRISPR/Cas9 KO, cDNA rescue (HAVCR1 and mHavcr1 transfection), HAV infection assay Journal of virology High 29437974
2017 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. CRISPR/Cas9 TIM-1 KO, ectopic expression rescue, PS liposome competition, anti-PS immunoprecipitation of HCV particles, siRNA knockdown Journal of virology High 27807228
2014 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. HAVCR1 overexpression and siRNA silencing, microarray, STAT-3 phosphorylation assay, HIF-1A measurement, ectodomain shedding assay Cancer research Medium 24390735
2011 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. Anti-TIM-1 mAb stimulation of DCs, flow cytometry (costimulatory molecules), cytokine measurement, in vivo EAE model with high- vs. low-avidity antibodies European journal of immunology Medium 21469101
2009 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. Soluble receptor neutralization and alteration assays, ion substitution experiments, temperature and pH variation, wt HAV cell culture system Virology journal Medium 19860892
2011 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. Flow cytometry (TIM-1/TIM-3 expression on mast cells), recombinant TIM-4 stimulation of bone marrow-derived mast cells, cytokine ELISA, degranulation assay Blood Medium 17620455
2022 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. 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 medRxivpreprint Medium 32995803
2018 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. CRISPR/Cas9 αDG knockout, pseudovirus transduction assay, IgV domain mutagenesis, mAb ARD5 blocking assay, chimeric TIM-1 rescue Journal of virology Medium 29875238
2019 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. Confocal microscopy (TIM-1/autophagosome co-localization), siRNA knockdown of TIM-1 and p85, GFP-LC3 autophagy reporter, co-localization at Rab5 endosomes International journal of molecular sciences Medium 31581681
2018 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. TIM-1 expression in human oligodendrocytes, Sema4A apoptosis assay, H-ferritin uptake assay, TIM-1 blocking experiments Glia Medium 29457657
2012 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. Site-directed mutagenesis of epsilon toxin, cell binding assay, HAVCR1 binding assay, cytotoxicity assay, circular dichroism spectroscopy Biochemistry Medium 22938730
2011 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. 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 Biochemical and biophysical research communications Medium 21303660
2022 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. CRISPR-mediated gene deletion in human expanded B cells, STAT3 signaling assay, T cell suppression assay, humanized mouse skin transplant model Nature communications Medium 35660734

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 528 18082433
2005 TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nature immunology 264 15793575
2018 Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion. Journal for immunotherapy of cancer 243 30526680
2013 Role of the phosphatidylserine receptor TIM-1 in enveloped-virus entry. Journal of virology 212 23698310
1998 The human homolog of HAVcr-1 codes for a hepatitis A virus cellular receptor. Journal of virology 174 9658108
2007 TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells. Blood 143 17620455
2003 Chromosome cohesion is regulated by a clock gene paralogue TIM-1. Nature 139 12827206
2015 Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses. Proceedings of the National Academy of Sciences of the United States of America 114 26575624
2015 Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. Journal of immunology (Baltimore, Md. : 1950) 113 25582854
2003 TIM-1, a novel allergy and asthma susceptibility gene. Springer seminars in immunopathology 107 15007635
2008 Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice. The Journal of clinical investigation 103 18079964
2017 Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm. mBio 95 28951472
2018 TIM-1 Ubiquitination Mediates Dengue Virus Entry. Cell reports 94 29742433
2012 Anti-CD45RB/anti-TIM-1-induced tolerance requires regulatory B cells. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 93 22494812
2017 TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients. Arthritis research & therapy 86 28103916
2008 Severe tuberculosis induces unbalanced up-regulation of gene networks and overexpression of IL-22, MIP-1alpha, CCL27, IP-10, CCR4, CCR5, CXCR3, PD1, PDL2, IL-3, IFN-beta, TIM1, and TLR2 but low antigen-specific cellular responses. The Journal of infectious diseases 83 18811584
2015 KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation. The EMBO journal 82 26282792
2010 TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury. The Journal of experimental medicine 81 20566714
2015 TIM-1 signaling is required for maintenance and induction of regulatory B cells. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 79 25645598
2014 HAVCR/KIM-1 activates the IL-6/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome. Cancer research 73 24390735
2011 A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans. The Journal of clinical investigation 70 21339644
2015 Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus. Journal of virology 66 25855742
2018 TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus. Journal of virology 65 29875238
2017 TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions. mBio 65 28874468
2009 Tipin/Tim1/And1 protein complex promotes Pol alpha chromatin binding and sister chromatid cohesion. The EMBO journal 65 19893489
2008 Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scandinavian journal of immunology 65 18052965
2007 Human TIM-1 associates with the TCR complex and up-regulates T cell activation signals. Journal of immunology (Baltimore, Md. : 1950) 65 17371991
2021 Regulatory B cells: TIM-1, transplant tolerance, and rejection. Immunological reviews 64 33484008
2005 Developmental timing in C. elegans is regulated by kin-20 and tim-1, homologs of core circadian clock genes. Developmental cell 63 15691769
2012 Kim-1/Tim-1 and immune cells: shifting sands. Kidney international 62 22499138
2008 TIM-1 and TIM-3 proteins in immune regulation. Cytokine 61 18706830
2014 TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity 60 24703780
2018 Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: A novel neuro-immune axis. Glia 59 29457657
2020 Checkpoint Receptor TIGIT Expressed on Tim-1+ B Cells Regulates Tissue Inflammation. Cell reports 56 32668241
2003 The association of the exon 4 variations of Tim-1 gene with allergic diseases in a Korean population. Biochemical and biophysical research communications 56 14637143
2009 Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. Proceedings of the National Academy of Sciences of the United States of America 54 19528638
2022 KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney. medRxiv : the preprint server for health sciences 53 32995803
2020 Exosome mimicry by a HAVCR1-NPC1 pathway of endosomal fusion mediates hepatitis A virus infection. Nature microbiology 53 32541946
2016 Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice. Arteriosclerosis, thrombosis, and vascular biology 51 26821944
2011 The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury. Journal of the American Society of Nephrology : JASN 49 21355054
2011 Novel roles for TIM-1 in immunity and infection. Immunology letters 49 21911007
2012 Identification of amino acids important for binding of Clostridium perfringens epsilon toxin to host cells and to HAVCR1. Biochemistry 48 22938730
2018 TIM-1 Promotes Japanese Encephalitis Virus Entry and Infection. Viruses 46 30441759
2011 Tim-1 promotes cisplatin nephrotoxicity. American journal of physiology. Renal physiology 45 21835770
2022 TIM-1 promotes proliferation and metastasis, and inhibits apoptosis, in cervical cancer through the PI3K/AKT/p53 pathway. BMC cancer 44 35392845
2020 Gastrointestinal digestion of dietary advanced glycation endproducts using an in vitro model of the gastrointestinal tract (TIM-1). Food & function 44 32602872
2011 Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells. European journal of immunology 44 21469101
2004 The polymorphisms of Tim-1 promoter region are associated with rheumatoid arthritis in a Korean population. Immunogenetics 44 15565336
2015 TIM-1 acts a dual-attachment receptor for Ebolavirus by interacting directly with viral GP and the PS on the viral envelope. Protein & cell 42 26487564
2019 TIM-1 serves as a receptor for Ebola virus in vivo, enhancing viremia and pathogenesis. PLoS neglected tropical diseases 41 31242184
2012 Targeting TIM-1 on CD4 T cells depresses macrophage activation and overcomes ischemia-reperfusion injury in mouse orthotopic liver transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 39 23137033
2010 Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma. The Journal of clinical investigation 39 20628202
2021 The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry. Cells 37 34359995
2017 Bacillus coagulans GBI-30, 6086 increases plant protein digestion in a dynamic, computer-controlled in vitro model of the small intestine (TIM-1). Beneficial microbes 37 28504581
2017 IL-21/anti-Tim1/CD40 ligand promotes B10 activity in vitro and alleviates bone loss in experimental periodontitis in vivo. Biochimica et biophysica acta. Molecular basis of disease 36 28583714
2017 TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection. Journal of virology 35 27807228
2004 The exon 4 variations of Tim-1 gene are associated with rheumatoid arthritis in a Korean population. Biochemical and biophysical research communications 35 14985107
2011 Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis. Kidney international 34 22205357
2021 Altered Tim-1 and IL-10 Expression in Regulatory B Cell Subsets in Type 1 Diabetes. Frontiers in immunology 33 35754999
2007 Immunoglobulin A (IgA) is a natural ligand of hepatitis A virus cellular receptor 1 (HAVCR1), and the association of IgA with HAVCR1 enhances virus-receptor interactions. Journal of virology 33 17229699
2022 Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis. Nature communications 31 35660734
2016 Immune Regulation and Antitumor Effect of TIM-1. Journal of immunology research 29 27413764
2009 Tim-1 signaling substitutes for conventional signal 1 and requires costimulation to induce T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 29 19155484
2005 Evidence for natural selection in the HAVCR1 gene: high degree of amino-acid variability in the mucin domain of human HAVCR1 protein. Genes and immunity 28 15889130
2009 Specific immunotherapy suppresses Th2 responses via modulating TIM1/TIM4 interaction on dendritic cells. Allergy 27 20028372
2010 Association between TIM-1 gene polymorphisms and allergic rhinitis in a Han Chinese population. Journal of investigational allergology & clinical immunology 26 20232767
2019 TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy. International journal of molecular sciences 25 31581681
2017 TIM4-TIM1 interaction modulates Th2 pattern inflammation through enhancing SIRT1 expression. International journal of molecular medicine 25 28949386
2012 Tim-1 regulates Th2 responses in an airway hypersensitivity model. European journal of immunology 23 22144095
2007 A functional polymorphism in the TIM-1 gene is associated with asthma in a Chinese Han population. International archives of allergy and immunology 23 17570927
2012 Polymorphisms of the TIM-1 gene are associated with rheumatoid arthritis in the Chinese Hui minority ethnic population. Genetics and molecular research : GMR 22 22290466
2022 miR-142 Targets TIM-1 in Human Endothelial Cells: Potential Implications for Stroke, COVID-19, Zika, Ebola, Dengue, and Other Viral Infections. International journal of molecular sciences 21 36142146
2017 Tim-1+ B cells suppress T cell interferon-gamma production and promote Foxp3 expression, but have impaired regulatory function in coronary artery disease. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 21 28736945
2006 TIM-1 regulates macrophage cytokine production and B7 family member expression. Immunology letters 21 17161870
2018 Association between the TIMD4-HAVCR1 variants and serum lipid levels, coronary heart disease and ischemic stroke risk and atorvastatin lipid-lowering efficacy. Bioscience reports 20 29208769
2011 TIM-1 signaling in B cells regulates antibody production. Biochemical and biophysical research communications 20 21303660
2016 Essential Roles of TIM-1 and TIM-4 Homologs in Adaptive Humoral Immunity in a Zebrafish Model. Journal of immunology (Baltimore, Md. : 1950) 19 26792807
2011 Fyn binds to and phosphorylates T cell immunoglobulin and mucin domain-1 (Tim-1). Molecular immunology 19 21513984
2023 The phosphatidylserine receptor TIM1 promotes infection of enveloped hepatitis E virus. Cellular and molecular life sciences : CMLS 18 37833515
2019 Inhibition of T cell immunoglobulin and mucin-1 (TIM-1) protects against cerebral ischemia-reperfusion injury. Cell communication and signaling : CCS 18 31438964
2018 Anti-TIM-1 Monoclonal Antibody (RMT1-10) Attenuates Atherosclerosis By Expanding IgM-producing B1a Cells. Journal of the American Heart Association 18 29936416
2013 HAVcR-1 expression in human colorectal cancer and its effects on colorectal cancer cells in vitro. Anticancer research 18 23267147
2012 Sequence and expression of per, tim1, and cry2 genes in the Madeira cockroach Rhyparobia maderae. Journal of biological rhythms 18 23223371
2010 TIM1 haplotype may control the disease progression to AIDS in a HIV-1-infected female cohort in Thailand. AIDS (London, England) 18 20479636
2008 Correlation between humoral and cellular immune responses and the expression of the hepatitis A receptor HAVcr-1 on T cells after hepatitis A re-vaccination in high and low-responder vaccinees. Vaccine 18 18996424
2011 Polymorphisms of the TIM-1 and TIM-3 genes are not associated with systemic lupus erythematosus in a Chinese population. Mutagenesis 17 21367814
2008 Significant association between TIM1 promoter polymorphisms and protection against cerebral malaria in Thailand. Annals of human genetics 17 18294362
2018 CD27+TIM-1+ memory B cells promoted the development of Foxp3+ Tregs and were associated with better survival in acute respiratory distress syndrome. Immunologic research 16 29392553
2018 HAVCR1 (CD365) and Its Mouse Ortholog Are Functional Hepatitis A Virus (HAV) Cellular Receptors That Mediate HAV Infection. Journal of virology 16 29437974
2018 MiR-15a/16-1 deficiency induces IL-10-producing CD19+ TIM-1+ cells in tumor microenvironment. Journal of cellular and molecular medicine 16 30467955
2009 Family-based association study of Tim-1 and Tim-3 gene polymorphisms with childhood asthma in Chinese trios. International archives of allergy and immunology 16 19494522
2007 The role of the T-cell costimulatory molecule Tim-1 in the immune response. Immunologic research 16 17917055
2020 Histone Methylation Inhibitor DZNep Ameliorated the Renal Ischemia-Reperfusion Injury via Inhibiting TIM-1 Mediated T Cell Activation. Frontiers in medicine 15 32754604
2013 Expression of Tim-1 and Tim-3 in Plasmodium berghei ANKA infection. Parasitology research 15 23653017
2011 Tim1 and Tim3 are not essential for experimental allergic asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 15 21470319
2022 Identification of a PD-L1+Tim-1+ iNKT subset that protects against fine particulate matter-induced airway inflammation. JCI insight 14 36477357
2019 HAVCR1 Affects the MEK/ERK Pathway in Gastric Adenocarcinomas and Influences Tumor Progression and Patient Outcome. Gastroenterology research and practice 14 31885544
2016 Expression of Tim-1 in primary CNS lymphoma. Cancer medicine 14 27709813
2009 The interaction of hepatitis A virus (HAV) with soluble forms of its cellular receptor 1 (HAVCR1) share the physiological requirements of infectivity in cell culture. Virology journal 14 19860892
2013 Variants in HAVCR1 gene region contribute to hepatitis C persistence in African Americans. The Journal of infectious diseases 13 23964107