{"gene":"CD300LF","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2011,"finding":"CD300f (mouse CD300f/LMIR3) binds phosphatidylserine (PS) exposed on the outer membrane of apoptotic cells, requiring a metal ion, and ectopic CD300f expression enhances phagocytosis of apoptotic cells by myeloid cells.","method":"ELISA, cosedimentation, surface plasmon resonance with phospholipid-containing liposomes; Annexin V competition; flow cytometry phagocytosis assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biophysical assays (SPR, cosedimentation, ELISA) plus functional phagocytosis readout in a single study","pmids":["21865548"],"is_preprint":false},{"year":2004,"finding":"IREM-1 (human CD300f ortholog) recruits SHP-1 via its cytoplasmic ITIM, with phosphotyrosine Y205 as the primary docking site, and cross-linking IREM-1 inhibits FcεRI-induced activation in myeloid cells.","method":"Yeast three-hybrid screen; Western blot; immunoprecipitation; Y205 mutagenesis; functional degranulation assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — binding partner identified by two-hybrid, confirmed by co-IP/Western, supported by site mutagenesis and functional inhibition assay","pmids":["15549731"],"is_preprint":false},{"year":2007,"finding":"CD300f (IREM-1) cytoplasmic domain recruits both p85α (PI3K regulatory subunit) and SHP-1; ITIMs Y205 and Y249 are required for inhibitory function, while Y236 and Y263 mediate PI3K recruitment and can drive activating signals when ITIMs are mutated.","method":"Immunoprecipitation in transfected cells and U937 monocytic cells; IREM-1 tyrosine mutants; RBL cell degranulation assay; PI3K inhibitors (wortmannin, LY-294002)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal co-IP confirmed in two cell systems, multiple tyrosine mutants, and pharmacologic inhibition with defined functional readout","pmids":["17202342"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the IREM-1 (human CD300f) extracellular Ig-V domain determined at 2.6 Å; CDR3-equivalent loop identified as the structurally variable region likely mediating ligand discrimination; three cavities form a continuous hydrophobic groove as a potential ligand-binding surface.","method":"X-ray crystallography (2.6 Å resolution); structural comparison with CLM-1, TREM-1, TLT-1, NKp44","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with structural functional inference, replicated across two crystallography papers","pmids":["17275839","17329815"],"is_preprint":false},{"year":2014,"finding":"CD300f accumulates in phagocytic cups at apoptotic cell contact sites; phosphorylation of Y276 in the cytoplasmic tail recruits p85α (PI3K regulatory subunit), activating Rac/Cdc42 GTPases and driving F-actin remodeling required for apoptotic cell engulfment; CD300f-deficient macrophages show impaired efferocytosis and CD300f-deficient mice develop lupus-like autoimmunity.","method":"Confocal microscopy (phagocytic cup localization); phosphotyrosine mutants; co-immunoprecipitation of p85α; Rac/Cdc42 activation assay; F-actin staining; CD300f-KO mouse phenotype with FcγRIIB-KO cross","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods: live imaging, mutagenesis, co-IP, GTPase assay, and in vivo KO phenotype in one study","pmids":["24477292"],"is_preprint":false},{"year":2016,"finding":"CD300f and CD300ld function as murine norovirus (MNoV) cell-surface receptors; ectopic CD300lf expression in non-susceptible cell lines confers MNoV permissibility; anti-CD300lf antibody blocks viral progeny production.","method":"Genome-wide CRISPR/Cas9 screen; ectopic expression in non-susceptible cell lines; antibody blocking assay; progeny virus quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genome-wide genetic screen plus gain-of-function and antibody blockade across multiple cell lines","pmids":["27681626"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of soluble CD300lf in complex with the MNoV VP1 protruding (P) domain determined at 2.05 Å; CD300lf binds with 2:2 stoichiometry at a cleft between AB and DE loops of P2 subdomain overlapping neutralizing antibody epitopes; engagement mimics host phosphocholine ligand binding including metal coordination; bile acids bind at a separate site on the P domain dimer interface and act as cofactors.","method":"X-ray crystallography (2.05 Å); biophysical assays (SPR, ITC); interface residue mutagenesis; cryo-EM docking; co-crystallization with bile acids GCDCA and LCA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution structure with mutagenesis and multiple biophysical validations, independently replicated by a second crystal structure paper","pmids":["30194229","29563286"],"is_preprint":false},{"year":2020,"finding":"CD300lf is the essential physiologic receptor for MNoV in vivo; CD300lf-deficient mice are fully resistant to both oral and parenteral MNoV infection and fail to mount anti-MNoV humoral responses; human CD300lf does not serve as a receptor for human norovirus.","method":"CD300lf global knockout mice; oral and parenteral infection models; STAT1-deficient/CD300lf-deficient cross; huCD300lf overexpression in cell culture with HNoV VLPs","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo genetic models with defined virological and immunological readouts","pmids":["32251490"],"is_preprint":false},{"year":2021,"finding":"CD300lf expression on intestinal tuft cells is essential for persistent MNoV (CR6) transmission in vivo; myelomonocytic cells are the primary but not exclusive target cells for non-persistent MNoV (CW3); STAT1 signaling restricts MNoV cell tropism independently of LysM+ CD300lf expression.","method":"Conditional CD300lf knockout mice using cell-type-specific Cre drivers (Villin, DCLK1, LysM, CD19, Mrp8, CD11c); in vivo infection with quantitative RT-PCR for viral load","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO across multiple Cre drivers with defined in vivo phenotypes","pmids":["33177207"],"is_preprint":false},{"year":2009,"finding":"CLM-1 (mouse CD300f ortholog) acts as a negative regulator of myeloid effector cell activity in autoimmune demyelination; CLM-1 deficiency increases nitric oxide and pro-inflammatory cytokine production and worsens EAE clinical scores without affecting peripheral T cell responses.","method":"CLM-1-deficient mice in MOG35-55 EAE model; cytokine/NO measurement; T cell response analysis; immunohistochemistry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype and pathway specificity (myeloid, not T cell)","pmids":["20038601"],"is_preprint":false},{"year":2011,"finding":"CD300F inhibits both MyD88- and TRIF-mediated TLR signaling in human monocytic cells through SHP-1 activation, suppressing IκBα kinase activation, IκB phosphorylation/degradation, and NF-κB activation.","method":"Anti-CD300F mAb crosslinking and ITIM synthetic peptides; luciferase NF-κB reporter in 293T cells; Western blot for IKK/IκB/NF-κB; SHP-1 inhibitors; immunoprecipitation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple approaches (antibody, peptides, reporter assay, inhibitors, co-IP) in one study establishing pathway position","pmids":["21536801"],"is_preprint":false},{"year":2015,"finding":"CD300f is co-localized and physically associated with IL-4Rα on myeloid cells; CD300f amplifies IL-4Rα-induced signaling, mediator release, and priming; Cd300f-deficient mice show decreased IgE production and reduced airway inflammation after allergen challenge.","method":"Co-immunoprecipitation; colocalization microscopy; receptor cross-linking; Cd300f-/- mice in allergen model with cytokine and IgE measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus in vivo KO phenotype with multiple readouts","pmids":["26124135"],"is_preprint":false},{"year":2015,"finding":"Ceramide binding to CD300f (LMIR3) inhibits ATP/P2X7-mediated mast cell activation; LMIR3 deficiency exacerbates DSS-induced colitis in a mast cell-dependent manner; ceramide liposomes suppress colitis through ceramide-LMIR3 interaction.","method":"LMIR3-/- mice; mast cell-deficient mice with WT or LMIR3-/- BMMC reconstitution; ELISA for mediators from ATP-stimulated BMMCs ± ceramide; ceramide liposome/anti-ceramide antibody administration in colitis model","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacologic approaches with cell-specific reconstitution establishing mast cell and ceramide-CD300f axis","pmids":["25673319"],"is_preprint":false},{"year":2013,"finding":"CLM-1 (CD300f) negatively regulates eotaxin-induced eosinophil chemotaxis, actin polymerization, calcium influx, and ERK1/2 phosphorylation; phosphatidylserine engagement of CLM-1 renders eosinophils hypochemotactic in vitro and in vivo.","method":"Clm1-/- mice (baseline eosinophilia phenotype); in vitro chemotaxis, actin polymerization, calcium flux, ERK phosphorylation assays; PS liposome treatment; CLM-1 blocking in allergic airway disease model","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse phenotype plus in vitro mechanistic assays with defined phospholipid ligand","pmids":["23820751"],"is_preprint":false},{"year":2016,"finding":"In dendritic cells (DCs), CD300f expression inhibits efferocytosis; CD300f-deficient DCs display hyperactive phagocytosis of apoptotic cells, stimulating excessive TNF-α secretion that drives secondary IFN-γ production by colonic T cells and prolonged gut inflammation.","method":"CD300f-KO mice in DSS colitis model; DC-specific phagocytosis assay; TNF-α and IFN-γ measurements; apoptotic cell accumulation in gut","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with cell-type-specific phagocytosis readout and defined cytokine pathway","pmids":["28414292"],"is_preprint":false},{"year":2016,"finding":"CD300f function in macrophages (promotes efferocytosis) is opposite to its function in dendritic cells (inhibits efferocytosis); CD300f deficiency in DCs leads to enhanced antigen processing, T cell priming, and expansion of memory T cells predisposing to autoimmunity.","method":"CD300f-KO mice; cell-type-specific efferocytosis assays; T cell priming and ANA measurements in aged mice; apoptotic cell overload and FcγRIIB-deficiency cross","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — KO phenotype with cell-type specificity established, but mechanism of cell-type-specific regulation not fully resolved","pmids":["26768664"],"is_preprint":false},{"year":2008,"finding":"Cross-linking CD300LF (MAIR-V) induces caspase-independent, ER-stress-independent cell death in peritoneal macrophages and transfectants; cell death requires the cytoplasmic region but not the ITIM or ITSM motifs.","method":"Anti-CD300LF mAb crosslinking; caspase inhibitor (z-VAD-fmk); autophagy inhibitors; ER stress marker (XBP-1 splicing); scanning electron microscopy; cytoplasmic domain deletion mutants","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with multiple inhibitors and domain mutants; single study","pmids":["18097021"],"is_preprint":false},{"year":2012,"finding":"CD300a blocks only MyD88-mediated TLR signaling via SHP-1, whereas CD300f blocks both MyD88- and TRIF-mediated TLR signaling through combined activation of SHP-1 and SHP-2.","method":"TLR ligand stimulation of THP-1 and U937 cells; ITIM synthetic peptides; luciferase reporter (NF-κB); Western blot; signaling inhibitors","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic comparison using multiple ligands, inhibitors, and reporters; single lab","pmids":["22043923"],"is_preprint":false},{"year":2004,"finding":"IgSF13 (human CD300f-related protein encoded on chromosome 17q25.2) upon pervanadate treatment is hyper-phosphorylated and recruits SHP-1 and SHIP (but not SHP-2) via its ITIMs.","method":"Pervanadate treatment; co-immunoprecipitation; Western blot","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP experiment; IgSF13 is a related but distinct protein","pmids":["15184070"],"is_preprint":false},{"year":2017,"finding":"Ceramide binding to CD300f suppresses LPS-induced mast cell and neutrophil mediator release, reducing skin edema and neutrophil recruitment in vivo; disrupting ceramide-CD300f interaction exacerbates LPS-induced skin inflammation.","method":"CD300f-/- mice; mast cell-deficient mice with BMMC reconstitution; adoptive neutrophil transfer; ceramide antibody and ceramide vesicle administration; mediator ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — cell-specific reconstitution experiments plus pharmacological ceramide manipulation, establishing ligand-receptor axis in vivo","pmids":["28073916"],"is_preprint":false},{"year":2017,"finding":"Ceramide-CD300f interaction inhibits ATP-stimulated mast cell neutrophil chemoattractant production; disrupting this interaction in a CLP sepsis model augments neutrophil recruitment and bacterial clearance, protecting from septic death.","method":"CD300f-/- mice; mast cell-deficient mice with WT or CD300f-/- BMMC transfer; CLP model; ceramide vesicle/anti-ceramide antibody administration; ELISA for chemoattractants and bacterial colony counts","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — cell-specific reconstitution and pharmacologic disruption in well-defined in vivo model","pmids":["28655892"],"is_preprint":false},{"year":2018,"finding":"LMIR3/CD300f negatively regulates neutrophil antimicrobial activity; LMIR3-KO neutrophils show increased hypochlorous acid production, elastase release, and cytotoxic activity against P. aeruginosa and C. albicans; LMIR3 expression on neutrophils increases in response to P. aeruginosa infection in a TLR4/MyD88-dependent manner.","method":"LMIR3-KO mice; in vitro neutrophil killing assays; elastase/myeloperoxidase inhibitors; in vivo Pseudomonas peritonitis and systemic candidiasis models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO phenotype with defined cellular mechanism; single lab","pmids":["30479367"],"is_preprint":false},{"year":2023,"finding":"CD300f signaling in human monocytes activates the PI3K/Akt pathway, upregulates PD-L1 (CD274), and promotes M2-type macrophage polarization; PI3K/Akt inhibition abrogates CD300f-driven PD-L1 upregulation.","method":"Anti-CD300f mAb (DCR-2) crosslinking; flow cytometry; PI3K/Akt inhibitors; T cell proliferation suppression assay; M1/M2 polarization markers","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — defined signaling pathway with pharmacologic inhibition and functional T cell readout; single lab","pmids":["37302321"],"is_preprint":false},{"year":2025,"finding":"CD300f on macrophages mediates engulfment of Rickettsia species by recognizing bacterial phosphatidylserine as ligand; CD300f-/- macrophages show reduced engulfment of R. typhi, R. rickettsii, and R. montanensis; CD300f-/- mice are protected from lethal rickettsiosis.","method":"CD300f-/- bone marrow-derived macrophages; in vivo infection of WT and KO mice; adoptive transfer of CD300f-expressing macrophages; bacterial burden quantification","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 — KO macrophages plus in vivo KO plus adoptive transfer establishing cell-autonomous CD300f-PS axis in bacterial engulfment","pmids":["40310290"],"is_preprint":false},{"year":2025,"finding":"CD300lf and CD300a cooperate to inhibit FcεRI-mediated mast cell activation; both receptors co-localize with PS externalized to the outer leaflet upon activation; CD300lf binding to extracellular ceramide produces stronger MC inhibition than PS binding alone; double-KO mice show more severe anaphylaxis than single KOs.","method":"Imaging and flow cytometry of BMMCs from WT, Cd300a-/-, Cd300lf-/-, Cd300a-/-Cd300lf-/- mice; passive systemic anaphylaxis model; colocalization with PS and ceramide","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — double-KO genetic epistasis with defined in vitro and in vivo phenotypes; ligand specificity distinguished by colocalization","pmids":["40073110"],"is_preprint":false},{"year":2025,"finding":"CD300f-deficient microglia fail to extend processes toward laser-induced cortical lesions (impaired damage sensing); show reduced recognition and clearance of apoptotic cells; retain apoptotic remnants indicating defective phagolysosomal processing; proteomic analysis reveals dysregulation of autophagy-related and metabolic pathways; ENTPD6 upregulation and P2ry6 mRNA downregulation suggest disrupted UDP-P2RY6 purinergic signaling axis underlying impaired phagocytic initiation.","method":"Intravital two-photon microscopy; CD300f-/- mice; mTBI and intracortical apoptotic cell injection models; controlled cortical injury contusion model; proteomics; RT-PCR; in vitro BMDM phagolysosomal assay","journal":"Brain, behavior, and immunity","confidence":"High","confidence_rationale":"Tier 1-2 — intravital imaging plus proteomics plus multiple in vivo models in one study providing strong mechanistic evidence","pmids":["40935207"],"is_preprint":false},{"year":2020,"finding":"A nonsynonymous SNP (rs2034310, C/T) in the human CD300f cytoplasmic tail inhibits protein kinase C phosphorylation of a threonine residue and is associated with protection against major depressive disorder; CD300f-/- mice display impaired microglial metabolic fitness and depressive/anhedonic behaviors in females.","method":"Human genetic association (rs2034310); PKC phosphorylation site analysis; CD300f-/- mouse behavioral phenotyping; RNA sequencing and biochemical metabolic studies of microglia","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic variant linked to defined PTM with in vivo KO phenotype, but mechanistic connection between PKC phosphorylation and microglial metabolism is inferred rather than directly demonstrated","pmids":["32152116"],"is_preprint":false},{"year":2024,"finding":"CD300LF-positive microglia impede neuroinflammation after traumatic brain injury principally by inhibiting the STING signaling pathway; CD300LF-deficient mice show increased glial proliferation, greater neuronal loss, and worse neurological function post-TBI.","method":"CD300LF-deficient mice; TBI model; transcriptomic comparison between CD300LF+ and CD300LF- microglia; STING pathway inhibitor (C-176) rescue","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — KO phenotype with transcriptomic pathway identification and pharmacologic rescue; single lab","pmids":["38965803"],"is_preprint":false},{"year":2020,"finding":"Polymorphisms in the CD300LF CC' loop (4-amino-acid difference between C57BL/6J and I/LnJ strains) determine MNoV receptor function in a cell-type-dependent manner; I/LnJ CD300LF does not function as MNoV receptor in macrophage-like cells but supports infection in other cell types.","method":"Bone marrow-derived macrophages from multiple inbred mouse strains; transduction with chimeric CD300LF constructs; virus binding assay; site-directed mutagenesis of CC' loop residues","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — domain-swap mutagenesis with functional infection and binding assays identifying critical CC' loop residues","pmids":["32581099"],"is_preprint":false}],"current_model":"CD300f (CD300LF) is a myeloid cell-expressed immunoreceptor with dual signaling capacity: its extracellular Ig-V domain binds phosphatidylserine, ceramide, and (in mice) the MNoV capsid, while its cytoplasmic ITIMs recruit SHP-1/SHP-2 to inhibit TLR/FcεRI/NF-κB signaling, and a PI3K-binding site (Y276 in mouse) recruits p85α to activate Rac/Cdc42-driven actin remodeling for apoptotic cell phagocytosis; cell-type context determines whether CD300f promotes (macrophages) or inhibits (dendritic cells) efferocytosis, and CD300lf serves as the sole physiologic receptor for murine norovirus through a structurally defined 2:2 interaction with the viral P domain."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing CD300f as an ITIM-bearing inhibitory receptor resolved how this orphan immunoglobulin superfamily member transduces signals, identifying SHP-1 recruitment via phospho-Y205 and functional suppression of FcεRI activation.","evidence":"Yeast three-hybrid screen, co-IP, Y205 mutagenesis, and degranulation assay in myeloid cells","pmids":["15549731"],"confidence":"High","gaps":["SHP-2 recruitment not yet tested","Endogenous ligand unknown","In vivo relevance of FcεRI inhibition not assessed"]},{"year":2007,"claim":"Demonstrating that distinct cytoplasmic tyrosines mediate opposing signals—ITIMs for inhibition via SHP-1 and non-ITIM tyrosines for activation via PI3K p85α—established CD300f as a dual-function signaling receptor whose output depends on which motifs are engaged.","evidence":"Systematic tyrosine mutants in transfected cells and U937 monocytes; co-IP of p85α; PI3K inhibitor experiments; crystal structure of the Ig-V domain at 2.6 Å","pmids":["17202342","17275839","17329815"],"confidence":"High","gaps":["No endogenous ligand identified","Structural basis of ligand binding not resolved","Cell-type-specific signaling balance unexplored"]},{"year":2009,"claim":"Defining CD300f as a negative regulator of myeloid effector responses in autoimmune demyelination established its in vivo immunosuppressive role, showing that loss increases NO and pro-inflammatory cytokines without affecting T cell priming.","evidence":"CLM-1-deficient mice in MOG-EAE model with cytokine, NO, and T cell analysis","pmids":["20038601"],"confidence":"High","gaps":["Ligand driving inhibition in EAE not identified","Downstream signaling pathway in CNS myeloid cells not mapped","Contribution of individual signaling motifs unknown"]},{"year":2011,"claim":"Identification of phosphatidylserine as the extracellular ligand, together with mapping CD300f's inhibitory action to both MyD88- and TRIF-dependent TLR pathways via SHP-1/NF-κB suppression, connected ligand recognition to a defined signaling cascade for the first time.","evidence":"SPR, cosedimentation, and ELISA with PS-containing liposomes; antibody crosslinking and ITIM peptides with NF-κB reporter, IKK/IκB Western blots, and SHP-1 inhibitors in monocytic cells","pmids":["21865548","21536801"],"confidence":"High","gaps":["Ceramide binding not yet recognized","Whether PS engagement drives inhibitory or activating arm not distinguished","In vivo relevance of PS-driven TLR inhibition not tested"]},{"year":2013,"claim":"Showing that PS–CD300f engagement suppresses eosinophil chemotaxis, actin polymerization, and ERK signaling extended the receptor's inhibitory function beyond mast cells and macrophages to granulocyte migration.","evidence":"Clm1-/- mice with baseline eosinophilia; in vitro chemotaxis, Ca²⁺ flux, ERK assays; PS liposome treatment; allergic airway model","pmids":["23820751"],"confidence":"High","gaps":["Whether inhibition is SHP-1- or SHP-2-dependent in eosinophils not tested","Contribution of ceramide not assessed"]},{"year":2014,"claim":"Demonstrating that CD300f accumulates in phagocytic cups and that Y276-p85α-Rac/Cdc42-F-actin signaling drives apoptotic cell engulfment resolved how the activating arm operates mechanistically; CD300f-KO mice developing lupus-like disease established efferocytosis failure as a disease-relevant consequence.","evidence":"Confocal imaging, phosphotyrosine mutants, co-IP of p85α, Rac/Cdc42 GTPase assays, and CD300f-KO/FcγRIIB-KO mice","pmids":["24477292"],"confidence":"High","gaps":["How inhibitory and activating arms are balanced in the same cell not resolved","Whether lupus phenotype maps to macrophage or DC efferocytosis defect unknown"]},{"year":2015,"claim":"Identification of ceramide as a second lipid ligand, and demonstration that ceramide–CD300f interaction inhibits ATP/P2X7-mediated mast cell activation and suppresses colitis, revealed a distinct anti-inflammatory axis beyond PS recognition; separately, physical association with IL-4Rα showed CD300f amplifies type-2 cytokine signaling.","evidence":"LMIR3-/- and mast-cell-deficient mice with BMMC reconstitution; ceramide liposomes in DSS colitis; co-IP of CD300f/IL-4Rα; allergen challenge in Cd300f-/- mice","pmids":["25673319","26124135"],"confidence":"High","gaps":["Structural basis of ceramide vs PS selectivity unknown","Whether IL-4Rα association requires PS/ceramide engagement untested","Relative contribution of PS and ceramide in vivo unclear"]},{"year":2016,"claim":"Discovery that CD300f promotes efferocytosis in macrophages but inhibits it in dendritic cells resolved the apparent paradox of pro- vs anti-inflammatory KO phenotypes, establishing cell-type context as the critical determinant of receptor output; simultaneously, CD300lf was identified as the entry receptor for murine norovirus by genome-wide CRISPR screen.","evidence":"Cell-type-specific phagocytosis assays in CD300f-KO mice with colitis/autoimmunity models; CRISPR screen with gain-of-function and antibody blockade for MNoV","pmids":["28414292","26768664","27681626"],"confidence":"High","gaps":["Molecular mechanism of cell-type-specific signaling not identified","Post-entry steps of MNoV infection through CD300lf unknown","Whether human CD300f shares DC-specific inhibitory function untested"]},{"year":2017,"claim":"Extension of the ceramide–CD300f inhibitory axis to neutrophils and mast cells in skin inflammation and sepsis demonstrated that disrupting this interaction could be either harmful (exacerbating inflammation) or beneficial (enhancing bacterial clearance), revealing context-dependent therapeutic implications.","evidence":"CD300f-/- and mast-cell-deficient mice with BMMC reconstitution and adoptive neutrophil transfer; ceramide vesicle and anti-ceramide antibody in LPS skin and CLP sepsis models","pmids":["28073916","28655892"],"confidence":"High","gaps":["How ceramide release is regulated during infection not addressed","Ceramide species specificity not resolved"]},{"year":2018,"claim":"Atomic-resolution crystal structure of CD300lf bound to the MNoV P domain defined the 2:2 binding stoichiometry, identified the CC' and DE loop interface overlapping neutralizing epitopes, revealed metal-coordinated mimicry of phosphocholine binding, and showed bile acids act as cofactors at a distinct site.","evidence":"X-ray crystallography at 2.05 Å; SPR and ITC; interface mutagenesis; co-crystallization with bile acids GCDCA and LCA","pmids":["30194229","29563286"],"confidence":"High","gaps":["Structural basis of ceramide binding to CD300f not determined","How bile acid cofactor activity operates mechanistically in vivo not fully resolved"]},{"year":2020,"claim":"Genetic proof that CD300lf is the sole physiologic MNoV receptor in vivo was established by complete resistance of CD300lf-KO mice to oral and parenteral infection; CC' loop polymorphisms between mouse strains were shown to determine receptor function in a cell-type-dependent manner; a human CD300f variant (rs2034310) affecting PKC phosphorylation was linked to major depressive disorder and microglial metabolic fitness.","evidence":"CD300lf global KO mice with oral/parenteral MNoV; chimeric CD300lf domain-swap mutagenesis across inbred strains; human GWAS with PKC phosphorylation analysis and CD300f-KO mouse behavioral/metabolic phenotyping","pmids":["32251490","32581099","32152116"],"confidence":"High","gaps":["Human CD300f does not serve as human norovirus receptor—human norovirus receptor identity remains open","How PKC phosphorylation of CD300f regulates microglial metabolism mechanistically unknown","Cell-type determinants of CC' loop polymorphism sensitivity not identified"]},{"year":2021,"claim":"Conditional KO studies pinpointed intestinal tuft cells as the CD300lf-expressing cells essential for persistent MNoV transmission and myelomonocytic cells as primary targets for acute strains, establishing cell-type-specific tropism determinants.","evidence":"Conditional CD300lf KO with Villin-Cre, DCLK1-Cre, LysM-Cre, and other Cre drivers; in vivo infection with qRT-PCR viral load","pmids":["33177207"],"confidence":"High","gaps":["What determines CD300lf expression levels in tuft cells vs myeloid cells unknown","Post-entry replication steps in tuft cells not characterized"]},{"year":2024,"claim":"Identification of STING signaling as a downstream pathway inhibited by CD300LF in microglia after traumatic brain injury provided a new mechanistic link between CD300f and innate nucleic acid sensing in the CNS.","evidence":"CD300LF-KO mice in TBI model; transcriptomic comparison; STING inhibitor (C-176) rescue of neurological deficits","pmids":["38965803"],"confidence":"Medium","gaps":["Direct biochemical connection between CD300f ITIM signaling and STING pathway not demonstrated","Whether SHP-1/SHP-2 mediate STING suppression not tested","Single lab finding"]},{"year":2025,"claim":"Intravital imaging and proteomics in CD300f-KO mice revealed that CD300f is required for microglial damage sensing, process extension, apoptotic cell recognition, and phagolysosomal processing, with disrupted purinergic (UDP-P2RY6) signaling as an underlying mechanism; separately, CD300f and CD300a were shown to cooperate in inhibiting mast cell activation, with ceramide producing stronger inhibition than PS; and CD300f was identified as a macrophage receptor exploited by Rickettsia species via bacterial PS.","evidence":"Two-photon intravital microscopy with mTBI and apoptotic cell injection models; proteomics and RT-PCR; double-KO (Cd300a/Cd300lf) mice in anaphylaxis; CD300f-KO macrophages with Rickettsia infection and adoptive transfer","pmids":["40935207","40073110","40310290"],"confidence":"High","gaps":["Whether purinergic signaling disruption is a direct consequence of CD300f loss or secondary to metabolic changes is unclear","Structural basis of cooperative CD300a/CD300f signaling unknown","Whether Rickettsia PS exposure is an active immune evasion strategy not established"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for ceramide versus PS discrimination by CD300f; the molecular mechanism underlying opposite efferocytosis outcomes in macrophages versus dendritic cells; whether the CD300f-STING and CD300f-purinergic axes represent direct signaling connections or indirect consequences; and identification of the human norovirus receptor.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structure with ceramide","No cell-type-specific signaling complex characterized","Human norovirus receptor unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,10,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,12,19]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[5,6,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,24]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9,10,13,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16]}],"complexes":[],"partners":["SHP-1","SHP-2","PIK3R1","IL4R","CD300A"],"other_free_text":[]},"mechanistic_narrative":"CD300LF (CD300f/CLM-1/LMIR3/IREM-1) is a myeloid-lineage immunomodulatory receptor whose extracellular Ig-V domain engages phosphatidylserine and ceramide on apoptotic or activated cells, and whose cytoplasmic tail integrates inhibitory and activating signals to govern innate immune effector functions, efferocytosis, and pathogen entry. Its tandem ITIMs (Y205, Y249 in human) recruit SHP-1 and SHP-2 to suppress FcεRI, TLR/MyD88/TRIF–NF-κB, and STING signaling cascades, dampening mast cell degranulation, eosinophil chemotaxis, neutrophil antimicrobial activity, and neuroinflammation [PMID:15549731, PMID:21536801, PMID:22043923, PMID:23820751, PMID:30479367, PMID:38965803]; a distinct PI3K-binding motif (Y236/Y263 human; Y276 mouse) recruits p85α to activate Rac/Cdc42-driven actin remodeling for phagocytic cup formation, and this pathway also drives PD-L1 upregulation and M2 macrophage polarization [PMID:17202342, PMID:24477292, PMID:37302321]. The balance between inhibitory and activating outputs is cell-type-dependent—macrophages and microglia require CD300f for efficient efferocytosis and damage sensing, whereas in dendritic cells it restrains apoptotic cell uptake, and its loss leads to lupus-like autoimmunity or exacerbated colitis [PMID:24477292, PMID:28414292, PMID:26768664, PMID:40935207]. In mice, CD300lf also serves as the sole physiological receptor for murine norovirus, binding the viral P domain in a structurally defined 2:2 complex through its CC' loop, with bile acids acting as cofactors; CD300lf-deficient mice are fully resistant to MNoV infection [PMID:27681626, PMID:30194229, PMID:32251490, PMID:32581099]."},"prefetch_data":{"uniprot":{"accession":"Q8TDQ1","full_name":"CMRF35-like molecule 1","aliases":["CD300 antigen-like family member F","Immune receptor expressed on myeloid cells 1","IREM-1","Immunoglobulin superfamily member 13","IgSF13","NK inhibitory receptor"],"length_aa":290,"mass_kda":32.3,"function":"Acts as an inhibitory receptor for myeloid cells and mast cells (PubMed:15549731). Positively regulates the phagocytosis of apoptotic cells (efferocytosis) via phosphatidylserine (PS) recognition; recognizes and binds PS as a ligand which is expressed on the surface of apoptotic cells. Plays an important role in the maintenance of immune homeostasis, by promoting macrophage-mediated efferocytosis and by inhibiting dendritic cell-mediated efferocytosis (By similarity). Negatively regulates Fc epsilon receptor-dependent mast cell activation and allergic responses via binding to ceramide and sphingomyelin which act as ligands (PubMed:24035150). May act as a coreceptor for interleukin 4 (IL-4). Associates with and regulates IL-4 receptor alpha-mediated responses by augmenting IL-4- and IL-13-induced signaling (By similarity). Negatively regulates the Toll-like receptor (TLR) signaling mediated by MYD88 and TRIF through activation of PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:22043923). Inhibits osteoclast formation. Induces macrophage cell death upon engagement (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TDQ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD300LF","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD300LF","total_profiled":1310},"omim":[{"mim_id":"616301","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER D; CD300LD","url":"https://www.omim.org/entry/616301"},{"mim_id":"610705","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER B; CD300LB","url":"https://www.omim.org/entry/610705"},{"mim_id":"609807","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER F; CD300LF","url":"https://www.omim.org/entry/609807"},{"mim_id":"609801","title":"CD300E ANTIGEN; CD300E","url":"https://www.omim.org/entry/609801"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":25.5},{"tissue":"lung","ntpm":16.6},{"tissue":"lymphoid tissue","ntpm":28.5}],"url":"https://www.proteinatlas.org/search/CD300LF"},"hgnc":{"alias_symbol":["IREM1","NKIR","IGSF13","CD300f","CLM1"],"prev_symbol":[]},"alphafold":{"accession":"Q8TDQ1","domains":[{"cath_id":"2.60.40.10","chopping":"21-129","consensus_level":"medium","plddt":98.0808,"start":21,"end":129}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDQ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDQ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDQ1-F1-predicted_aligned_error_v6.png","plddt_mean":72.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD300LF","jax_strain_url":"https://www.jax.org/strain/search?query=CD300LF"},"sequence":{"accession":"Q8TDQ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TDQ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TDQ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDQ1"}},"corpus_meta":[{"pmid":"27681626","id":"PMC_27681626","title":"Functional 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millet.","date":"2025","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/40394337","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32025,"output_tokens":7070,"usd":0.101062},"stage2":{"model":"claude-opus-4-6","input_tokens":10834,"output_tokens":4198,"usd":0.23868},"total_usd":0.339742,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"CD300f (mouse CD300f/LMIR3) binds phosphatidylserine (PS) exposed on the outer membrane of apoptotic cells, requiring a metal ion, and ectopic CD300f expression enhances phagocytosis of apoptotic cells by myeloid cells.\",\n      \"method\": \"ELISA, cosedimentation, surface plasmon resonance with phospholipid-containing liposomes; Annexin V competition; flow cytometry phagocytosis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biophysical assays (SPR, cosedimentation, ELISA) plus functional phagocytosis readout in a single study\",\n      \"pmids\": [\"21865548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IREM-1 (human CD300f ortholog) recruits SHP-1 via its cytoplasmic ITIM, with phosphotyrosine Y205 as the primary docking site, and cross-linking IREM-1 inhibits FcεRI-induced activation in myeloid cells.\",\n      \"method\": \"Yeast three-hybrid screen; Western blot; immunoprecipitation; Y205 mutagenesis; functional degranulation assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — binding partner identified by two-hybrid, confirmed by co-IP/Western, supported by site mutagenesis and functional inhibition assay\",\n      \"pmids\": [\"15549731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD300f (IREM-1) cytoplasmic domain recruits both p85α (PI3K regulatory subunit) and SHP-1; ITIMs Y205 and Y249 are required for inhibitory function, while Y236 and Y263 mediate PI3K recruitment and can drive activating signals when ITIMs are mutated.\",\n      \"method\": \"Immunoprecipitation in transfected cells and U937 monocytic cells; IREM-1 tyrosine mutants; RBL cell degranulation assay; PI3K inhibitors (wortmannin, LY-294002)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP confirmed in two cell systems, multiple tyrosine mutants, and pharmacologic inhibition with defined functional readout\",\n      \"pmids\": [\"17202342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the IREM-1 (human CD300f) extracellular Ig-V domain determined at 2.6 Å; CDR3-equivalent loop identified as the structurally variable region likely mediating ligand discrimination; three cavities form a continuous hydrophobic groove as a potential ligand-binding surface.\",\n      \"method\": \"X-ray crystallography (2.6 Å resolution); structural comparison with CLM-1, TREM-1, TLT-1, NKp44\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with structural functional inference, replicated across two crystallography papers\",\n      \"pmids\": [\"17275839\", \"17329815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD300f accumulates in phagocytic cups at apoptotic cell contact sites; phosphorylation of Y276 in the cytoplasmic tail recruits p85α (PI3K regulatory subunit), activating Rac/Cdc42 GTPases and driving F-actin remodeling required for apoptotic cell engulfment; CD300f-deficient macrophages show impaired efferocytosis and CD300f-deficient mice develop lupus-like autoimmunity.\",\n      \"method\": \"Confocal microscopy (phagocytic cup localization); phosphotyrosine mutants; co-immunoprecipitation of p85α; Rac/Cdc42 activation assay; F-actin staining; CD300f-KO mouse phenotype with FcγRIIB-KO cross\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods: live imaging, mutagenesis, co-IP, GTPase assay, and in vivo KO phenotype in one study\",\n      \"pmids\": [\"24477292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD300f and CD300ld function as murine norovirus (MNoV) cell-surface receptors; ectopic CD300lf expression in non-susceptible cell lines confers MNoV permissibility; anti-CD300lf antibody blocks viral progeny production.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen; ectopic expression in non-susceptible cell lines; antibody blocking assay; progeny virus quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide genetic screen plus gain-of-function and antibody blockade across multiple cell lines\",\n      \"pmids\": [\"27681626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of soluble CD300lf in complex with the MNoV VP1 protruding (P) domain determined at 2.05 Å; CD300lf binds with 2:2 stoichiometry at a cleft between AB and DE loops of P2 subdomain overlapping neutralizing antibody epitopes; engagement mimics host phosphocholine ligand binding including metal coordination; bile acids bind at a separate site on the P domain dimer interface and act as cofactors.\",\n      \"method\": \"X-ray crystallography (2.05 Å); biophysical assays (SPR, ITC); interface residue mutagenesis; cryo-EM docking; co-crystallization with bile acids GCDCA and LCA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution structure with mutagenesis and multiple biophysical validations, independently replicated by a second crystal structure paper\",\n      \"pmids\": [\"30194229\", \"29563286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD300lf is the essential physiologic receptor for MNoV in vivo; CD300lf-deficient mice are fully resistant to both oral and parenteral MNoV infection and fail to mount anti-MNoV humoral responses; human CD300lf does not serve as a receptor for human norovirus.\",\n      \"method\": \"CD300lf global knockout mice; oral and parenteral infection models; STAT1-deficient/CD300lf-deficient cross; huCD300lf overexpression in cell culture with HNoV VLPs\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo genetic models with defined virological and immunological readouts\",\n      \"pmids\": [\"32251490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD300lf expression on intestinal tuft cells is essential for persistent MNoV (CR6) transmission in vivo; myelomonocytic cells are the primary but not exclusive target cells for non-persistent MNoV (CW3); STAT1 signaling restricts MNoV cell tropism independently of LysM+ CD300lf expression.\",\n      \"method\": \"Conditional CD300lf knockout mice using cell-type-specific Cre drivers (Villin, DCLK1, LysM, CD19, Mrp8, CD11c); in vivo infection with quantitative RT-PCR for viral load\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO across multiple Cre drivers with defined in vivo phenotypes\",\n      \"pmids\": [\"33177207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CLM-1 (mouse CD300f ortholog) acts as a negative regulator of myeloid effector cell activity in autoimmune demyelination; CLM-1 deficiency increases nitric oxide and pro-inflammatory cytokine production and worsens EAE clinical scores without affecting peripheral T cell responses.\",\n      \"method\": \"CLM-1-deficient mice in MOG35-55 EAE model; cytokine/NO measurement; T cell response analysis; immunohistochemistry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype and pathway specificity (myeloid, not T cell)\",\n      \"pmids\": [\"20038601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD300F inhibits both MyD88- and TRIF-mediated TLR signaling in human monocytic cells through SHP-1 activation, suppressing IκBα kinase activation, IκB phosphorylation/degradation, and NF-κB activation.\",\n      \"method\": \"Anti-CD300F mAb crosslinking and ITIM synthetic peptides; luciferase NF-κB reporter in 293T cells; Western blot for IKK/IκB/NF-κB; SHP-1 inhibitors; immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple approaches (antibody, peptides, reporter assay, inhibitors, co-IP) in one study establishing pathway position\",\n      \"pmids\": [\"21536801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD300f is co-localized and physically associated with IL-4Rα on myeloid cells; CD300f amplifies IL-4Rα-induced signaling, mediator release, and priming; Cd300f-deficient mice show decreased IgE production and reduced airway inflammation after allergen challenge.\",\n      \"method\": \"Co-immunoprecipitation; colocalization microscopy; receptor cross-linking; Cd300f-/- mice in allergen model with cytokine and IgE measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus in vivo KO phenotype with multiple readouts\",\n      \"pmids\": [\"26124135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ceramide binding to CD300f (LMIR3) inhibits ATP/P2X7-mediated mast cell activation; LMIR3 deficiency exacerbates DSS-induced colitis in a mast cell-dependent manner; ceramide liposomes suppress colitis through ceramide-LMIR3 interaction.\",\n      \"method\": \"LMIR3-/- mice; mast cell-deficient mice with WT or LMIR3-/- BMMC reconstitution; ELISA for mediators from ATP-stimulated BMMCs ± ceramide; ceramide liposome/anti-ceramide antibody administration in colitis model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacologic approaches with cell-specific reconstitution establishing mast cell and ceramide-CD300f axis\",\n      \"pmids\": [\"25673319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CLM-1 (CD300f) negatively regulates eotaxin-induced eosinophil chemotaxis, actin polymerization, calcium influx, and ERK1/2 phosphorylation; phosphatidylserine engagement of CLM-1 renders eosinophils hypochemotactic in vitro and in vivo.\",\n      \"method\": \"Clm1-/- mice (baseline eosinophilia phenotype); in vitro chemotaxis, actin polymerization, calcium flux, ERK phosphorylation assays; PS liposome treatment; CLM-1 blocking in allergic airway disease model\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse phenotype plus in vitro mechanistic assays with defined phospholipid ligand\",\n      \"pmids\": [\"23820751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In dendritic cells (DCs), CD300f expression inhibits efferocytosis; CD300f-deficient DCs display hyperactive phagocytosis of apoptotic cells, stimulating excessive TNF-α secretion that drives secondary IFN-γ production by colonic T cells and prolonged gut inflammation.\",\n      \"method\": \"CD300f-KO mice in DSS colitis model; DC-specific phagocytosis assay; TNF-α and IFN-γ measurements; apoptotic cell accumulation in gut\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with cell-type-specific phagocytosis readout and defined cytokine pathway\",\n      \"pmids\": [\"28414292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD300f function in macrophages (promotes efferocytosis) is opposite to its function in dendritic cells (inhibits efferocytosis); CD300f deficiency in DCs leads to enhanced antigen processing, T cell priming, and expansion of memory T cells predisposing to autoimmunity.\",\n      \"method\": \"CD300f-KO mice; cell-type-specific efferocytosis assays; T cell priming and ANA measurements in aged mice; apoptotic cell overload and FcγRIIB-deficiency cross\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype with cell-type specificity established, but mechanism of cell-type-specific regulation not fully resolved\",\n      \"pmids\": [\"26768664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cross-linking CD300LF (MAIR-V) induces caspase-independent, ER-stress-independent cell death in peritoneal macrophages and transfectants; cell death requires the cytoplasmic region but not the ITIM or ITSM motifs.\",\n      \"method\": \"Anti-CD300LF mAb crosslinking; caspase inhibitor (z-VAD-fmk); autophagy inhibitors; ER stress marker (XBP-1 splicing); scanning electron microscopy; cytoplasmic domain deletion mutants\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with multiple inhibitors and domain mutants; single study\",\n      \"pmids\": [\"18097021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD300a blocks only MyD88-mediated TLR signaling via SHP-1, whereas CD300f blocks both MyD88- and TRIF-mediated TLR signaling through combined activation of SHP-1 and SHP-2.\",\n      \"method\": \"TLR ligand stimulation of THP-1 and U937 cells; ITIM synthetic peptides; luciferase reporter (NF-κB); Western blot; signaling inhibitors\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic comparison using multiple ligands, inhibitors, and reporters; single lab\",\n      \"pmids\": [\"22043923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IgSF13 (human CD300f-related protein encoded on chromosome 17q25.2) upon pervanadate treatment is hyper-phosphorylated and recruits SHP-1 and SHIP (but not SHP-2) via its ITIMs.\",\n      \"method\": \"Pervanadate treatment; co-immunoprecipitation; Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP experiment; IgSF13 is a related but distinct protein\",\n      \"pmids\": [\"15184070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ceramide binding to CD300f suppresses LPS-induced mast cell and neutrophil mediator release, reducing skin edema and neutrophil recruitment in vivo; disrupting ceramide-CD300f interaction exacerbates LPS-induced skin inflammation.\",\n      \"method\": \"CD300f-/- mice; mast cell-deficient mice with BMMC reconstitution; adoptive neutrophil transfer; ceramide antibody and ceramide vesicle administration; mediator ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-specific reconstitution experiments plus pharmacological ceramide manipulation, establishing ligand-receptor axis in vivo\",\n      \"pmids\": [\"28073916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ceramide-CD300f interaction inhibits ATP-stimulated mast cell neutrophil chemoattractant production; disrupting this interaction in a CLP sepsis model augments neutrophil recruitment and bacterial clearance, protecting from septic death.\",\n      \"method\": \"CD300f-/- mice; mast cell-deficient mice with WT or CD300f-/- BMMC transfer; CLP model; ceramide vesicle/anti-ceramide antibody administration; ELISA for chemoattractants and bacterial colony counts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-specific reconstitution and pharmacologic disruption in well-defined in vivo model\",\n      \"pmids\": [\"28655892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LMIR3/CD300f negatively regulates neutrophil antimicrobial activity; LMIR3-KO neutrophils show increased hypochlorous acid production, elastase release, and cytotoxic activity against P. aeruginosa and C. albicans; LMIR3 expression on neutrophils increases in response to P. aeruginosa infection in a TLR4/MyD88-dependent manner.\",\n      \"method\": \"LMIR3-KO mice; in vitro neutrophil killing assays; elastase/myeloperoxidase inhibitors; in vivo Pseudomonas peritonitis and systemic candidiasis models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype with defined cellular mechanism; single lab\",\n      \"pmids\": [\"30479367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD300f signaling in human monocytes activates the PI3K/Akt pathway, upregulates PD-L1 (CD274), and promotes M2-type macrophage polarization; PI3K/Akt inhibition abrogates CD300f-driven PD-L1 upregulation.\",\n      \"method\": \"Anti-CD300f mAb (DCR-2) crosslinking; flow cytometry; PI3K/Akt inhibitors; T cell proliferation suppression assay; M1/M2 polarization markers\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined signaling pathway with pharmacologic inhibition and functional T cell readout; single lab\",\n      \"pmids\": [\"37302321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD300f on macrophages mediates engulfment of Rickettsia species by recognizing bacterial phosphatidylserine as ligand; CD300f-/- macrophages show reduced engulfment of R. typhi, R. rickettsii, and R. montanensis; CD300f-/- mice are protected from lethal rickettsiosis.\",\n      \"method\": \"CD300f-/- bone marrow-derived macrophages; in vivo infection of WT and KO mice; adoptive transfer of CD300f-expressing macrophages; bacterial burden quantification\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO macrophages plus in vivo KO plus adoptive transfer establishing cell-autonomous CD300f-PS axis in bacterial engulfment\",\n      \"pmids\": [\"40310290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD300lf and CD300a cooperate to inhibit FcεRI-mediated mast cell activation; both receptors co-localize with PS externalized to the outer leaflet upon activation; CD300lf binding to extracellular ceramide produces stronger MC inhibition than PS binding alone; double-KO mice show more severe anaphylaxis than single KOs.\",\n      \"method\": \"Imaging and flow cytometry of BMMCs from WT, Cd300a-/-, Cd300lf-/-, Cd300a-/-Cd300lf-/- mice; passive systemic anaphylaxis model; colocalization with PS and ceramide\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double-KO genetic epistasis with defined in vitro and in vivo phenotypes; ligand specificity distinguished by colocalization\",\n      \"pmids\": [\"40073110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD300f-deficient microglia fail to extend processes toward laser-induced cortical lesions (impaired damage sensing); show reduced recognition and clearance of apoptotic cells; retain apoptotic remnants indicating defective phagolysosomal processing; proteomic analysis reveals dysregulation of autophagy-related and metabolic pathways; ENTPD6 upregulation and P2ry6 mRNA downregulation suggest disrupted UDP-P2RY6 purinergic signaling axis underlying impaired phagocytic initiation.\",\n      \"method\": \"Intravital two-photon microscopy; CD300f-/- mice; mTBI and intracortical apoptotic cell injection models; controlled cortical injury contusion model; proteomics; RT-PCR; in vitro BMDM phagolysosomal assay\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — intravital imaging plus proteomics plus multiple in vivo models in one study providing strong mechanistic evidence\",\n      \"pmids\": [\"40935207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A nonsynonymous SNP (rs2034310, C/T) in the human CD300f cytoplasmic tail inhibits protein kinase C phosphorylation of a threonine residue and is associated with protection against major depressive disorder; CD300f-/- mice display impaired microglial metabolic fitness and depressive/anhedonic behaviors in females.\",\n      \"method\": \"Human genetic association (rs2034310); PKC phosphorylation site analysis; CD300f-/- mouse behavioral phenotyping; RNA sequencing and biochemical metabolic studies of microglia\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic variant linked to defined PTM with in vivo KO phenotype, but mechanistic connection between PKC phosphorylation and microglial metabolism is inferred rather than directly demonstrated\",\n      \"pmids\": [\"32152116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD300LF-positive microglia impede neuroinflammation after traumatic brain injury principally by inhibiting the STING signaling pathway; CD300LF-deficient mice show increased glial proliferation, greater neuronal loss, and worse neurological function post-TBI.\",\n      \"method\": \"CD300LF-deficient mice; TBI model; transcriptomic comparison between CD300LF+ and CD300LF- microglia; STING pathway inhibitor (C-176) rescue\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype with transcriptomic pathway identification and pharmacologic rescue; single lab\",\n      \"pmids\": [\"38965803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Polymorphisms in the CD300LF CC' loop (4-amino-acid difference between C57BL/6J and I/LnJ strains) determine MNoV receptor function in a cell-type-dependent manner; I/LnJ CD300LF does not function as MNoV receptor in macrophage-like cells but supports infection in other cell types.\",\n      \"method\": \"Bone marrow-derived macrophages from multiple inbred mouse strains; transduction with chimeric CD300LF constructs; virus binding assay; site-directed mutagenesis of CC' loop residues\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain-swap mutagenesis with functional infection and binding assays identifying critical CC' loop residues\",\n      \"pmids\": [\"32581099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD300f (CD300LF) is a myeloid cell-expressed immunoreceptor with dual signaling capacity: its extracellular Ig-V domain binds phosphatidylserine, ceramide, and (in mice) the MNoV capsid, while its cytoplasmic ITIMs recruit SHP-1/SHP-2 to inhibit TLR/FcεRI/NF-κB signaling, and a PI3K-binding site (Y276 in mouse) recruits p85α to activate Rac/Cdc42-driven actin remodeling for apoptotic cell phagocytosis; cell-type context determines whether CD300f promotes (macrophages) or inhibits (dendritic cells) efferocytosis, and CD300lf serves as the sole physiologic receptor for murine norovirus through a structurally defined 2:2 interaction with the viral P domain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD300LF (CD300f/CLM-1/LMIR3/IREM-1) is a myeloid-lineage immunomodulatory receptor whose extracellular Ig-V domain engages phosphatidylserine and ceramide on apoptotic or activated cells, and whose cytoplasmic tail integrates inhibitory and activating signals to govern innate immune effector functions, efferocytosis, and pathogen entry. Its tandem ITIMs (Y205, Y249 in human) recruit SHP-1 and SHP-2 to suppress FcεRI, TLR/MyD88/TRIF–NF-κB, and STING signaling cascades, dampening mast cell degranulation, eosinophil chemotaxis, neutrophil antimicrobial activity, and neuroinflammation [PMID:15549731, PMID:21536801, PMID:22043923, PMID:23820751, PMID:30479367, PMID:38965803]; a distinct PI3K-binding motif (Y236/Y263 human; Y276 mouse) recruits p85α to activate Rac/Cdc42-driven actin remodeling for phagocytic cup formation, and this pathway also drives PD-L1 upregulation and M2 macrophage polarization [PMID:17202342, PMID:24477292, PMID:37302321]. The balance between inhibitory and activating outputs is cell-type-dependent—macrophages and microglia require CD300f for efficient efferocytosis and damage sensing, whereas in dendritic cells it restrains apoptotic cell uptake, and its loss leads to lupus-like autoimmunity or exacerbated colitis [PMID:24477292, PMID:28414292, PMID:26768664, PMID:40935207]. In mice, CD300lf also serves as the sole physiological receptor for murine norovirus, binding the viral P domain in a structurally defined 2:2 complex through its CC' loop, with bile acids acting as cofactors; CD300lf-deficient mice are fully resistant to MNoV infection [PMID:27681626, PMID:30194229, PMID:32251490, PMID:32581099].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing CD300f as an ITIM-bearing inhibitory receptor resolved how this orphan immunoglobulin superfamily member transduces signals, identifying SHP-1 recruitment via phospho-Y205 and functional suppression of FcεRI activation.\",\n      \"evidence\": \"Yeast three-hybrid screen, co-IP, Y205 mutagenesis, and degranulation assay in myeloid cells\",\n      \"pmids\": [\"15549731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SHP-2 recruitment not yet tested\", \"Endogenous ligand unknown\", \"In vivo relevance of FcεRI inhibition not assessed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that distinct cytoplasmic tyrosines mediate opposing signals—ITIMs for inhibition via SHP-1 and non-ITIM tyrosines for activation via PI3K p85α—established CD300f as a dual-function signaling receptor whose output depends on which motifs are engaged.\",\n      \"evidence\": \"Systematic tyrosine mutants in transfected cells and U937 monocytes; co-IP of p85α; PI3K inhibitor experiments; crystal structure of the Ig-V domain at 2.6 Å\",\n      \"pmids\": [\"17202342\", \"17275839\", \"17329815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No endogenous ligand identified\", \"Structural basis of ligand binding not resolved\", \"Cell-type-specific signaling balance unexplored\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining CD300f as a negative regulator of myeloid effector responses in autoimmune demyelination established its in vivo immunosuppressive role, showing that loss increases NO and pro-inflammatory cytokines without affecting T cell priming.\",\n      \"evidence\": \"CLM-1-deficient mice in MOG-EAE model with cytokine, NO, and T cell analysis\",\n      \"pmids\": [\"20038601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving inhibition in EAE not identified\", \"Downstream signaling pathway in CNS myeloid cells not mapped\", \"Contribution of individual signaling motifs unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of phosphatidylserine as the extracellular ligand, together with mapping CD300f's inhibitory action to both MyD88- and TRIF-dependent TLR pathways via SHP-1/NF-κB suppression, connected ligand recognition to a defined signaling cascade for the first time.\",\n      \"evidence\": \"SPR, cosedimentation, and ELISA with PS-containing liposomes; antibody crosslinking and ITIM peptides with NF-κB reporter, IKK/IκB Western blots, and SHP-1 inhibitors in monocytic cells\",\n      \"pmids\": [\"21865548\", \"21536801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ceramide binding not yet recognized\", \"Whether PS engagement drives inhibitory or activating arm not distinguished\", \"In vivo relevance of PS-driven TLR inhibition not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that PS–CD300f engagement suppresses eosinophil chemotaxis, actin polymerization, and ERK signaling extended the receptor's inhibitory function beyond mast cells and macrophages to granulocyte migration.\",\n      \"evidence\": \"Clm1-/- mice with baseline eosinophilia; in vitro chemotaxis, Ca²⁺ flux, ERK assays; PS liposome treatment; allergic airway model\",\n      \"pmids\": [\"23820751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether inhibition is SHP-1- or SHP-2-dependent in eosinophils not tested\", \"Contribution of ceramide not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that CD300f accumulates in phagocytic cups and that Y276-p85α-Rac/Cdc42-F-actin signaling drives apoptotic cell engulfment resolved how the activating arm operates mechanistically; CD300f-KO mice developing lupus-like disease established efferocytosis failure as a disease-relevant consequence.\",\n      \"evidence\": \"Confocal imaging, phosphotyrosine mutants, co-IP of p85α, Rac/Cdc42 GTPase assays, and CD300f-KO/FcγRIIB-KO mice\",\n      \"pmids\": [\"24477292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How inhibitory and activating arms are balanced in the same cell not resolved\", \"Whether lupus phenotype maps to macrophage or DC efferocytosis defect unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of ceramide as a second lipid ligand, and demonstration that ceramide–CD300f interaction inhibits ATP/P2X7-mediated mast cell activation and suppresses colitis, revealed a distinct anti-inflammatory axis beyond PS recognition; separately, physical association with IL-4Rα showed CD300f amplifies type-2 cytokine signaling.\",\n      \"evidence\": \"LMIR3-/- and mast-cell-deficient mice with BMMC reconstitution; ceramide liposomes in DSS colitis; co-IP of CD300f/IL-4Rα; allergen challenge in Cd300f-/- mice\",\n      \"pmids\": [\"25673319\", \"26124135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ceramide vs PS selectivity unknown\", \"Whether IL-4Rα association requires PS/ceramide engagement untested\", \"Relative contribution of PS and ceramide in vivo unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that CD300f promotes efferocytosis in macrophages but inhibits it in dendritic cells resolved the apparent paradox of pro- vs anti-inflammatory KO phenotypes, establishing cell-type context as the critical determinant of receptor output; simultaneously, CD300lf was identified as the entry receptor for murine norovirus by genome-wide CRISPR screen.\",\n      \"evidence\": \"Cell-type-specific phagocytosis assays in CD300f-KO mice with colitis/autoimmunity models; CRISPR screen with gain-of-function and antibody blockade for MNoV\",\n      \"pmids\": [\"28414292\", \"26768664\", \"27681626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of cell-type-specific signaling not identified\", \"Post-entry steps of MNoV infection through CD300lf unknown\", \"Whether human CD300f shares DC-specific inhibitory function untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extension of the ceramide–CD300f inhibitory axis to neutrophils and mast cells in skin inflammation and sepsis demonstrated that disrupting this interaction could be either harmful (exacerbating inflammation) or beneficial (enhancing bacterial clearance), revealing context-dependent therapeutic implications.\",\n      \"evidence\": \"CD300f-/- and mast-cell-deficient mice with BMMC reconstitution and adoptive neutrophil transfer; ceramide vesicle and anti-ceramide antibody in LPS skin and CLP sepsis models\",\n      \"pmids\": [\"28073916\", \"28655892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ceramide release is regulated during infection not addressed\", \"Ceramide species specificity not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Atomic-resolution crystal structure of CD300lf bound to the MNoV P domain defined the 2:2 binding stoichiometry, identified the CC' and DE loop interface overlapping neutralizing epitopes, revealed metal-coordinated mimicry of phosphocholine binding, and showed bile acids act as cofactors at a distinct site.\",\n      \"evidence\": \"X-ray crystallography at 2.05 Å; SPR and ITC; interface mutagenesis; co-crystallization with bile acids GCDCA and LCA\",\n      \"pmids\": [\"30194229\", \"29563286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ceramide binding to CD300f not determined\", \"How bile acid cofactor activity operates mechanistically in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic proof that CD300lf is the sole physiologic MNoV receptor in vivo was established by complete resistance of CD300lf-KO mice to oral and parenteral infection; CC' loop polymorphisms between mouse strains were shown to determine receptor function in a cell-type-dependent manner; a human CD300f variant (rs2034310) affecting PKC phosphorylation was linked to major depressive disorder and microglial metabolic fitness.\",\n      \"evidence\": \"CD300lf global KO mice with oral/parenteral MNoV; chimeric CD300lf domain-swap mutagenesis across inbred strains; human GWAS with PKC phosphorylation analysis and CD300f-KO mouse behavioral/metabolic phenotyping\",\n      \"pmids\": [\"32251490\", \"32581099\", \"32152116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human CD300f does not serve as human norovirus receptor—human norovirus receptor identity remains open\", \"How PKC phosphorylation of CD300f regulates microglial metabolism mechanistically unknown\", \"Cell-type determinants of CC' loop polymorphism sensitivity not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Conditional KO studies pinpointed intestinal tuft cells as the CD300lf-expressing cells essential for persistent MNoV transmission and myelomonocytic cells as primary targets for acute strains, establishing cell-type-specific tropism determinants.\",\n      \"evidence\": \"Conditional CD300lf KO with Villin-Cre, DCLK1-Cre, LysM-Cre, and other Cre drivers; in vivo infection with qRT-PCR viral load\",\n      \"pmids\": [\"33177207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines CD300lf expression levels in tuft cells vs myeloid cells unknown\", \"Post-entry replication steps in tuft cells not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of STING signaling as a downstream pathway inhibited by CD300LF in microglia after traumatic brain injury provided a new mechanistic link between CD300f and innate nucleic acid sensing in the CNS.\",\n      \"evidence\": \"CD300LF-KO mice in TBI model; transcriptomic comparison; STING inhibitor (C-176) rescue of neurological deficits\",\n      \"pmids\": [\"38965803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical connection between CD300f ITIM signaling and STING pathway not demonstrated\", \"Whether SHP-1/SHP-2 mediate STING suppression not tested\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Intravital imaging and proteomics in CD300f-KO mice revealed that CD300f is required for microglial damage sensing, process extension, apoptotic cell recognition, and phagolysosomal processing, with disrupted purinergic (UDP-P2RY6) signaling as an underlying mechanism; separately, CD300f and CD300a were shown to cooperate in inhibiting mast cell activation, with ceramide producing stronger inhibition than PS; and CD300f was identified as a macrophage receptor exploited by Rickettsia species via bacterial PS.\",\n      \"evidence\": \"Two-photon intravital microscopy with mTBI and apoptotic cell injection models; proteomics and RT-PCR; double-KO (Cd300a/Cd300lf) mice in anaphylaxis; CD300f-KO macrophages with Rickettsia infection and adoptive transfer\",\n      \"pmids\": [\"40935207\", \"40073110\", \"40310290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether purinergic signaling disruption is a direct consequence of CD300f loss or secondary to metabolic changes is unclear\", \"Structural basis of cooperative CD300a/CD300f signaling unknown\", \"Whether Rickettsia PS exposure is an active immune evasion strategy not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for ceramide versus PS discrimination by CD300f; the molecular mechanism underlying opposite efferocytosis outcomes in macrophages versus dendritic cells; whether the CD300f-STING and CD300f-purinergic axes represent direct signaling connections or indirect consequences; and identification of the human norovirus receptor.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structure with ceramide\", \"No cell-type-specific signaling complex characterized\", \"Human norovirus receptor unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 10, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 12, 19]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 10, 13, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SHP-1\",\n      \"SHP-2\",\n      \"PIK3R1\",\n      \"IL4R\",\n      \"CD300A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}