{"gene":"CLEC4D","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"Human CLECSF8 (CLEC4D) is a type II membrane glycoprotein of 215 amino acids expressed in a monocyte/macrophage pattern. Cross-linking of the receptor leads to rapid internalization, establishing it as an endocytic receptor. Biochemical analysis showed it is a glycoprotein of ~30 kDa.","method":"Molecular cloning, Western blotting, cross-linking/internalization assay in transfected cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, direct biochemical characterization and internalization assay, but single method set without functional follow-up","pmids":["14971047"],"is_preprint":false},{"year":2012,"finding":"CLECSF8 (CLEC4D) is primarily expressed on peripheral blood neutrophils and monocytes, and is lost upon in vitro differentiation of monocytes into dendritic cells or macrophages. The C-type lectin domain (not the transmembrane domain) is responsible for intracellular retention when expressed in non-myeloid cells. CLECSF8 does not associate with DAP10, DAP12, or FcRγ chain. Despite lacking a cytoplasmic signaling motif, CLECSF8 triggers signaling via Syk kinase in myeloid cells and induces phagocytosis, proinflammatory cytokine production, and the respiratory burst, indicating it associates with a novel, unidentified adaptor molecule.","method":"Flow cytometry, co-immunoprecipitation (negative for known adaptors), reporter assays, functional assays (phagocytosis, cytokine production, respiratory burst), oligosaccharide microarrays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in a single lab; reciprocal Co-IP ruled out known adaptors, functional assays established Syk-dependent activation","pmids":["22689578"],"is_preprint":false},{"year":2013,"finding":"Dectin-3 (CLEC4D) recognizes α-mannans on the surface of Candida albicans hyphae and induces NF-κB activation. Dectin-3 constitutively forms heterodimers with Dectin-2, and the Dectin-3/Dectin-2 heterodimer binds α-mannans more effectively than either homodimer alone, leading to more potent inflammatory responses. Mice with blocked or genetically deleted Dectin-3 were highly susceptible to C. albicans infection.","method":"Co-immunoprecipitation (heterodimer formation), NF-κB reporter assay, ligand binding assays, Clec4d knockout mouse infection model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for heterodimer, functional reporter assay, in vivo genetic knockout, multiple orthogonal methods in single study","pmids":["23911656"],"is_preprint":false},{"year":2013,"finding":"Clec4d deficiency in mice results in higher bacterial burdens and increased mortality upon M. tuberculosis infection, with exacerbated pulmonary inflammation and enhanced neutrophil recruitment. Clecsf8-/- mice show reduced mycobacterial uptake by pulmonary leukocytes, which is restored by opsonization, identifying CLEC4D as a non-redundant phagocytic receptor in anti-mycobacterial immunity.","method":"Clec4d knockout mouse model, M. tuberculosis infection, bacterial burden measurement, flow cytometry, phagocytosis assay with opsonized bacteria","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes (bacterial burden, phagocytosis, neutrophil recruitment), multiple orthogonal readouts, replicated in human genetic association","pmids":["25674984"],"is_preprint":false},{"year":2013,"finding":"Clec4d (Dectin-3) deficiency in mice leads to increased susceptibility to DSS-induced colitis, associated with elevated gut burden of Candida tropicalis. Mechanistically, Dectin-3 deficiency impairs phagocytic and fungicidal abilities of macrophages, and reduces C. tropicalis-induced NF-κB activation and cytokine production. Conditioned media from Dectin-3-deficient macrophages was defective in promoting tissue repair in colonic epithelial cells.","method":"Clec4d knockout mouse DSS-colitis model, fungal burden measurement, macrophage phagocytosis and killing assays, NF-κB reporter assay, conditioned media tissue repair assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple defined cellular and molecular phenotypes across in vivo and in vitro assays","pmids":["27280399"],"is_preprint":false},{"year":2015,"finding":"MCL (CLEC4D) interacts with Mincle through its stalk region to promote Mincle surface expression post-translationally. After LPS or zymosan stimulation, MCL-deficient BMDCs had lower Mincle protein (but not mRNA) levels, while MCL transgenic BMDCs showed enhanced Mincle surface expression. The stalk region was necessary and sufficient, and substitution of four hydrophobic residues (MCL-4S mutant) abolished this function and failed to restore TDM responses in MCL-deficient BMDCs.","method":"Co-immunoprecipitation, flow cytometry (surface expression), Western blotting, MCL transgenic and knockout BMDC comparisons, domain mutagenesis (MCL-4S)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP for interaction, domain mutagenesis defining stalk region, gain- and loss-of-function genetics, functional rescue experiments","pmids":["25888641"],"is_preprint":false},{"year":2015,"finding":"Clec4d in mice is predominantly expressed on myeloid cells (peritoneal cavity, blood, bone marrow) with very low basal expression in lung leukocytes, but is strongly upregulated on pulmonary myeloid cells during M. bovis BCG infection. Clec4d expression requires association with the signaling adaptor FcRγ and Mincle (but not Dectin-2) for surface expression, and Clec4d and Mincle are interdependently co-regulated during inflammation. Microbial stimuli (TLR agonists) but not exogenous cytokines induced Clec4d expression.","method":"Monoclonal antibody-based flow cytometry, co-immunoprecipitation (FcRγ, Mincle), in vivo BCG infection, in vitro stimulation assays","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — newly generated monoclonal antibodies, Co-IP for adaptor association, in vivo infection model, multiple orthogonal methods","pmids":["26558717"],"is_preprint":false},{"year":2016,"finding":"Microbial stimulation triggers Mincle expression via the MyD88 pathway, independent of MCL (CLEC4D). Conversely, MCL is constitutively expressed but retained intracellularly until Mincle is induced, whereupon MCL and Mincle form heterodimers that are translocated to the cell surface. This establishes a two-step model for surface expression of MCL: MyD88-driven Mincle induction is required for MCL to reach the cell surface.","method":"Western blotting, flow cytometry, co-immunoprecipitation (heterodimer), MyD88-deficient cells, gene expression analysis","journal":"Microbes and infection","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and genetic (MyD88-KO) epistasis in single lab, two orthogonal methods","pmids":["27005451"],"is_preprint":false},{"year":2017,"finding":"Dectin-3 (CLEC4D) is not required for protection against Cryptococcus neoformans infection in a murine pulmonary model. Dectin-3-deficient mice showed no increased susceptibility, no differences in pulmonary leukocyte recruitment or cytokine production, and no defects in uptake or anti-cryptococcal activity of dendritic cells or macrophages — a negative mechanistic finding for this specific pathogen.","method":"Clec4d knockout mouse C. neoformans infection model, CFU measurement, flow cytometry, phagocytosis assay, cytokine measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple readouts, single lab; finding is a defined negative result for this pathogen context","pmids":["28107361"],"is_preprint":false},{"year":2013,"finding":"Clec4d (CLEC4D/MCL) plays a protective role in resolution of Gram-negative (Klebsiella pneumoniae) pneumonia. Clec4d-/- mice showed progressive bacterial burden and hyperinflammatory sepsis response, with massive neutrophil accumulation in lungs, while WT mice resolved infection. Clec4d-/- neutrophils did not exhibit a defect in bacterial clearance per se, suggesting Clec4d facilitates neutrophil turnover/resolution rather than direct bactericidal activity.","method":"Clec4d knockout mouse K. pneumoniae pneumonia model, bacterial burden measurement, lung histology, flow cytometry for neutrophil accumulation, in vitro bacterial killing assay","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype and mechanistic dissection (killing assay negative), single lab","pmids":["23709686"],"is_preprint":false}],"current_model":"CLEC4D (Dectin-3/MCL/CLECSF8) is a myeloid cell-expressed C-type lectin receptor that recognizes fungal α-mannans and mycobacterial trehalose dimycolate; it constitutively forms heterodimers with Mincle via its stalk region to promote Mincle surface expression and amplify signaling, requires FcRγ and Mincle for its own surface translocation (via a MyD88-driven two-step mechanism), and signals through Syk kinase in myeloid cells to drive phagocytosis, cytokine production, and NF-κB activation, with in vivo roles established in anti-fungal (C. albicans) and anti-mycobacterial (M. tuberculosis) immunity and in resolution of Gram-negative pneumonia."},"narrative":{"mechanistic_narrative":"CLEC4D (CLECSF8/Dectin-3/MCL) is a myeloid-expressed type II transmembrane C-type lectin receptor that functions as a pattern-recognition and phagocytic receptor in antimicrobial innate immunity [PMID:14971047, PMID:25674984]. It is displayed on neutrophils and monocytes and lost upon their differentiation into dendritic cells or macrophages, and its C-type lectin domain mediates ligand recognition and, in non-myeloid contexts, intracellular retention [PMID:22689578]. CLEC4D recognizes α-mannans on Candida albicans hyphae and drives NF-κB activation, and despite lacking a cytoplasmic signaling motif it triggers Syk-dependent phagocytosis, proinflammatory cytokine production, and the respiratory burst [PMID:22689578, PMID:23911656]. Its activity is organized through obligate partnership with Mincle: CLEC4D binds Mincle via its stalk region—four hydrophobic residues are required—to post-translationally stabilize and promote Mincle surface expression, and CLEC4D itself depends on FcRγ and Mincle for surface translocation through a two-step mechanism in which MyD88-driven microbial induction of Mincle licenses the CLEC4D/Mincle heterodimer to exit intracellular stores to the cell surface [PMID:25888641, PMID:26558717, PMID:27005451]. In vivo, CLEC4D is non-redundant for control of C. albicans and Mycobacterium tuberculosis infection and for resolution of Klebsiella pneumoniae pneumonia, where it governs neutrophil turnover rather than direct bacterial killing, but it is dispensable against Cryptococcus neoformans, defining pathogen-specific functional boundaries [PMID:23911656, PMID:25674984, PMID:28107361, PMID:23709686].","teleology":[{"year":2004,"claim":"Established CLEC4D as a monocyte/macrophage-restricted cell-surface glycoprotein capable of internalization, framing it as a candidate endocytic immune receptor before any ligand was known.","evidence":"Molecular cloning, Western blot, and cross-linking/internalization assay in transfected cells","pmids":["14971047"],"confidence":"Medium","gaps":["No ligand identified","No signaling pathway or adaptor defined","Endocytic function inferred from cross-linking, not physiological ligand"]},{"year":2012,"claim":"Resolved how a receptor lacking a cytoplasmic signaling motif transmits signals, showing CLEC4D activates Syk to drive phagocytosis, cytokine production, and respiratory burst while not using known adaptors, implying a novel adaptor partner.","evidence":"Flow cytometry, reciprocal Co-IP excluding DAP10/DAP12/FcRγ, reporter and functional assays, oligosaccharide microarrays in myeloid cells","pmids":["22689578"],"confidence":"Medium","gaps":["The adaptor coupling CLEC4D to Syk was not identified","Physiological ligand not defined here","Mechanism of Syk recruitment unresolved"]},{"year":2013,"claim":"Identified CLEC4D as an α-mannan receptor that heterodimerizes with Dectin-2 for enhanced ligand binding and NF-κB-driven inflammation, and demonstrated non-redundant in vivo roles spanning antifungal, antimycobacterial, and Gram-negative pneumonia resolution.","evidence":"Reciprocal Co-IP, NF-κB reporter and ligand-binding assays, Clec4d knockout mouse infection models (C. albicans, M. tuberculosis, K. pneumoniae)","pmids":["23911656","25674984","23709686"],"confidence":"High","gaps":["Whether Dectin-2 and Mincle partnerships are distinct or overlapping was not reconciled","Mechanism of neutrophil resolution in pneumonia not molecularly defined","Phagocytosis vs signaling contributions not separated in vivo"]},{"year":2016,"claim":"Extended the protective antifungal role to mucosal immunity, showing CLEC4D supports macrophage phagocytosis, killing, NF-κB activation, and tissue-repair signaling that constrains commensal fungal overgrowth in colitis.","evidence":"Clec4d knockout DSS-colitis model, fungal burden, macrophage phagocytosis/killing assays, NF-κB reporter, conditioned-media tissue repair assay","pmids":["27280399"],"confidence":"High","gaps":["Tissue-repair effector(s) in conditioned media not identified","Direct receptor-ligand engagement with C. tropicalis not structurally defined"]},{"year":2015,"claim":"Defined the molecular basis of the CLEC4D–Mincle partnership, mapping a stalk-region interaction (four hydrophobic residues) that post-translationally promotes Mincle surface expression and is required for TDM responses.","evidence":"Co-IP, surface flow cytometry, Western blot, MCL transgenic/knockout BMDCs, MCL-4S domain mutagenesis with functional rescue","pmids":["25888641"],"confidence":"High","gaps":["Structural detail of the stalk interface not resolved","How heterodimer stabilization translates to enhanced signaling not fully defined"]},{"year":2015,"claim":"Established that CLEC4D surface expression itself depends on FcRγ and Mincle and that CLEC4D and Mincle are interdependently co-regulated and microbially induced during infection.","evidence":"Monoclonal antibody flow cytometry, Co-IP for FcRγ/Mincle, in vivo BCG infection, TLR-agonist stimulation assays","pmids":["26558717"],"confidence":"High","gaps":["Mechanism of FcRγ requirement for surface delivery not detailed","Distinction between Mincle and Dectin-2 partnerships not reconciled"]},{"year":2016,"claim":"Integrated the regulatory logic into a two-step model in which MyD88-driven Mincle induction licenses constitutively expressed CLEC4D to exit intracellular stores as a CLEC4D/Mincle heterodimer to the surface.","evidence":"Western blot, flow cytometry, Co-IP, MyD88-deficient cells, gene expression epistasis","pmids":["27005451"],"confidence":"Medium","gaps":["Trafficking machinery mediating co-translocation not identified","Single-lab epistasis without orthogonal confirmation"]},{"year":2017,"claim":"Delimited the receptor's protective scope by showing CLEC4D is dispensable for control of Cryptococcus neoformans, indicating pathogen-specific rather than universal antimicrobial function.","evidence":"Clec4d knockout C. neoformans pulmonary infection, CFU, flow cytometry, phagocytosis and cytokine assays","pmids":["28107361"],"confidence":"Medium","gaps":["Does not exclude redundancy with other receptors for this pathogen","Negative result limited to the murine pulmonary context tested"]},{"year":null,"claim":"The structural basis of CLEC4D heterodimerization and its quantitative contribution to signaling versus phagocytosis in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CLEC4D alone or in heterodimer","Trafficking machinery for surface delivery unknown","Effectors mediating tissue repair and neutrophil resolution unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]}],"complexes":["CLEC4D/Mincle heterodimer","CLEC4D/Dectin-2 heterodimer"],"partners":["CLEC4E","CLEC6A","FCER1G","SYK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXI8","full_name":"C-type lectin domain family 4 member D","aliases":["C-type lectin superfamily member 8","C-type lectin-like receptor 6","CLEC-6","Dendritic cell-associated C-type lectin 3","DC-associated C-type lectin 3","Dectin-3"],"length_aa":215,"mass_kda":24.7,"function":"Calcium-dependent lectin that acts as a pattern recognition receptor (PRR) of the innate immune system: recognizes damage-associated molecular patterns (DAMPs) of pathogen-associated molecular patterns (PAMPs) of bacteria and fungi (PubMed:23602766, PubMed:23911656). The PAMPs include alpha-mannans on C.albicans hypheas and mycobacterial trehalose 6,6'-dimycolate (TDM) (PubMed:23602766, PubMed:23911656). Interacts with signaling adapter Fc receptor gamma chain/FCER1G, likely via CLEC4E, to form a functional complex in myeloid cells (By similarity). Binding of mycobacterial TDM or C.albicans alpha-mannans to this receptor complex leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of FCER1G, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (PubMed:23602766, PubMed:23911656). The heterodimer formed with CLEC6A is active against fungal infection (PubMed:23911656). Functions as an endocytic receptor (PubMed:14971047). May be involved in antigen uptake at the site of infection, either for clearance of the antigen, or for processing and further presentation to T-cells (PubMed:14971047)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8WXI8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLEC4D","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CLEC4D","total_profiled":1310},"omim":[{"mim_id":"619223","title":"IMMUNODEFICIENCY 77; IMD77","url":"https://www.omim.org/entry/619223"},{"mim_id":"613579","title":"C-TYPE LECTIN DOMAIN FAMILY 6, MEMBER A; CLEC6A","url":"https://www.omim.org/entry/613579"},{"mim_id":"609964","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER D; CLEC4D","url":"https://www.omim.org/entry/609964"},{"mim_id":"609962","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER E; CLEC4E","url":"https://www.omim.org/entry/609962"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":61.1}],"url":"https://www.proteinatlas.org/search/CLEC4D"},"hgnc":{"alias_symbol":["Mpcl","CD368","MCL","Dectin-3"],"prev_symbol":["CLECSF8"]},"alphafold":{"accession":"Q8WXI8","domains":[{"cath_id":"3.10.100.10","chopping":"59-215","consensus_level":"medium","plddt":91.3611,"start":59,"end":215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXI8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXI8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXI8-F1-predicted_aligned_error_v6.png","plddt_mean":86.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLEC4D","jax_strain_url":"https://www.jax.org/strain/search?query=CLEC4D"},"sequence":{"accession":"Q8WXI8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXI8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXI8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXI8"}},"corpus_meta":[{"pmid":"14668867","id":"PMC_14668867","title":"Development 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/20973747","citation_count":26,"is_preprint":false},{"pmid":"35349392","id":"PMC_35349392","title":"MCL-1 is a clinically targetable vulnerability in breast cancer.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/35349392","citation_count":25,"is_preprint":false},{"pmid":"31467029","id":"PMC_31467029","title":"CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax.","date":"2019","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31467029","citation_count":25,"is_preprint":false},{"pmid":"35563775","id":"PMC_35563775","title":"Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35563775","citation_count":25,"is_preprint":false},{"pmid":"29775995","id":"PMC_29775995","title":"Phosphorylation alters Bim-mediated 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transition.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24481815","citation_count":22,"is_preprint":false},{"pmid":"19763916","id":"PMC_19763916","title":"Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR.","date":"2009","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19763916","citation_count":22,"is_preprint":false},{"pmid":"36346691","id":"PMC_36346691","title":"Mechanisms of MCL-1 Protein Stability Induced by MCL-1 Antagonists in B-Cell Malignancies.","date":"2023","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/36346691","citation_count":21,"is_preprint":false},{"pmid":"36535926","id":"PMC_36535926","title":"Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36535926","citation_count":21,"is_preprint":false},{"pmid":"33336620","id":"PMC_33336620","title":"Epigenetic modulation of FBW7/Mcl-1 pathway for lung cancer therapy.","date":"2020","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33336620","citation_count":20,"is_preprint":false},{"pmid":"33512417","id":"PMC_33512417","title":"Requirement for antiapoptotic MCL-1 during early erythropoiesis.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/33512417","citation_count":20,"is_preprint":false},{"pmid":"30201826","id":"PMC_30201826","title":"Repurposing of mTOR Complex Inhibitors Attenuates MCL-1 and Sensitizes to PARP Inhibition.","date":"2018","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/30201826","citation_count":20,"is_preprint":false},{"pmid":"25756510","id":"PMC_25756510","title":"EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.","date":"2015","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/25756510","citation_count":20,"is_preprint":false},{"pmid":"33658484","id":"PMC_33658484","title":"Phosphatase PP2A enhances MCL-1 protein half-life in multiple myeloma cells.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33658484","citation_count":18,"is_preprint":false},{"pmid":"31735913","id":"PMC_31735913","title":"MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31735913","citation_count":18,"is_preprint":false},{"pmid":"28520795","id":"PMC_28520795","title":"BIRC6 mediates imatinib resistance independently of Mcl-1.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28520795","citation_count":18,"is_preprint":false},{"pmid":"32587776","id":"PMC_32587776","title":"DYRK1A suppression restrains Mcl-1 expression and sensitizes NSCLC cells to Bcl-2 inhibitors.","date":"2020","source":"Cancer biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32587776","citation_count":17,"is_preprint":false},{"pmid":"24260268","id":"PMC_24260268","title":"MCL-1ES induces MCL-1L-dependent BAX- and BAK-independent mitochondrial apoptosis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24260268","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46941,"output_tokens":3236,"usd":0.094682,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10393,"output_tokens":3235,"usd":0.06642,"stage2_stop_reason":"end_turn"},"total_usd":0.161102,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about CLEC4D (also known as CLECSF8, MCL, Dectin-3, Mpcl, CD368) — the C-type lectin receptor — versus papers about MCL-1 (myeloid cell leukemia-1), which is a BCL-2 family anti-apoptotic protein. These are completely different genes. The CLEC4D/MCL/Dectin-3 papers are about a C-type lectin receptor involved in innate immunity, while the vast majority of the corpus is about MCL-1 (BCL-2 family protein), which shares the \"MCL\" abbreviation but is a different gene (MCL1, not CLEC4D).\n\nI will extract only findings from papers about CLEC4D/CLECSF8/Dectin-3/MCL (C-type lectin receptor), which are papers [6], [24], [25], [27], [31], [39], [48], [60], [65], [76].\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Human CLECSF8 (CLEC4D) is a type II membrane glycoprotein of 215 amino acids expressed in a monocyte/macrophage pattern. Cross-linking of the receptor leads to rapid internalization, establishing it as an endocytic receptor. Biochemical analysis showed it is a glycoprotein of ~30 kDa.\",\n      \"method\": \"Molecular cloning, Western blotting, cross-linking/internalization assay in transfected cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, direct biochemical characterization and internalization assay, but single method set without functional follow-up\",\n      \"pmids\": [\"14971047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CLECSF8 (CLEC4D) is primarily expressed on peripheral blood neutrophils and monocytes, and is lost upon in vitro differentiation of monocytes into dendritic cells or macrophages. The C-type lectin domain (not the transmembrane domain) is responsible for intracellular retention when expressed in non-myeloid cells. CLECSF8 does not associate with DAP10, DAP12, or FcRγ chain. Despite lacking a cytoplasmic signaling motif, CLECSF8 triggers signaling via Syk kinase in myeloid cells and induces phagocytosis, proinflammatory cytokine production, and the respiratory burst, indicating it associates with a novel, unidentified adaptor molecule.\",\n      \"method\": \"Flow cytometry, co-immunoprecipitation (negative for known adaptors), reporter assays, functional assays (phagocytosis, cytokine production, respiratory burst), oligosaccharide microarrays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in a single lab; reciprocal Co-IP ruled out known adaptors, functional assays established Syk-dependent activation\",\n      \"pmids\": [\"22689578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dectin-3 (CLEC4D) recognizes α-mannans on the surface of Candida albicans hyphae and induces NF-κB activation. Dectin-3 constitutively forms heterodimers with Dectin-2, and the Dectin-3/Dectin-2 heterodimer binds α-mannans more effectively than either homodimer alone, leading to more potent inflammatory responses. Mice with blocked or genetically deleted Dectin-3 were highly susceptible to C. albicans infection.\",\n      \"method\": \"Co-immunoprecipitation (heterodimer formation), NF-κB reporter assay, ligand binding assays, Clec4d knockout mouse infection model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for heterodimer, functional reporter assay, in vivo genetic knockout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23911656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Clec4d deficiency in mice results in higher bacterial burdens and increased mortality upon M. tuberculosis infection, with exacerbated pulmonary inflammation and enhanced neutrophil recruitment. Clecsf8-/- mice show reduced mycobacterial uptake by pulmonary leukocytes, which is restored by opsonization, identifying CLEC4D as a non-redundant phagocytic receptor in anti-mycobacterial immunity.\",\n      \"method\": \"Clec4d knockout mouse model, M. tuberculosis infection, bacterial burden measurement, flow cytometry, phagocytosis assay with opsonized bacteria\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes (bacterial burden, phagocytosis, neutrophil recruitment), multiple orthogonal readouts, replicated in human genetic association\",\n      \"pmids\": [\"25674984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Clec4d (Dectin-3) deficiency in mice leads to increased susceptibility to DSS-induced colitis, associated with elevated gut burden of Candida tropicalis. Mechanistically, Dectin-3 deficiency impairs phagocytic and fungicidal abilities of macrophages, and reduces C. tropicalis-induced NF-κB activation and cytokine production. Conditioned media from Dectin-3-deficient macrophages was defective in promoting tissue repair in colonic epithelial cells.\",\n      \"method\": \"Clec4d knockout mouse DSS-colitis model, fungal burden measurement, macrophage phagocytosis and killing assays, NF-κB reporter assay, conditioned media tissue repair assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple defined cellular and molecular phenotypes across in vivo and in vitro assays\",\n      \"pmids\": [\"27280399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MCL (CLEC4D) interacts with Mincle through its stalk region to promote Mincle surface expression post-translationally. After LPS or zymosan stimulation, MCL-deficient BMDCs had lower Mincle protein (but not mRNA) levels, while MCL transgenic BMDCs showed enhanced Mincle surface expression. The stalk region was necessary and sufficient, and substitution of four hydrophobic residues (MCL-4S mutant) abolished this function and failed to restore TDM responses in MCL-deficient BMDCs.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry (surface expression), Western blotting, MCL transgenic and knockout BMDC comparisons, domain mutagenesis (MCL-4S)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP for interaction, domain mutagenesis defining stalk region, gain- and loss-of-function genetics, functional rescue experiments\",\n      \"pmids\": [\"25888641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Clec4d in mice is predominantly expressed on myeloid cells (peritoneal cavity, blood, bone marrow) with very low basal expression in lung leukocytes, but is strongly upregulated on pulmonary myeloid cells during M. bovis BCG infection. Clec4d expression requires association with the signaling adaptor FcRγ and Mincle (but not Dectin-2) for surface expression, and Clec4d and Mincle are interdependently co-regulated during inflammation. Microbial stimuli (TLR agonists) but not exogenous cytokines induced Clec4d expression.\",\n      \"method\": \"Monoclonal antibody-based flow cytometry, co-immunoprecipitation (FcRγ, Mincle), in vivo BCG infection, in vitro stimulation assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — newly generated monoclonal antibodies, Co-IP for adaptor association, in vivo infection model, multiple orthogonal methods\",\n      \"pmids\": [\"26558717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Microbial stimulation triggers Mincle expression via the MyD88 pathway, independent of MCL (CLEC4D). Conversely, MCL is constitutively expressed but retained intracellularly until Mincle is induced, whereupon MCL and Mincle form heterodimers that are translocated to the cell surface. This establishes a two-step model for surface expression of MCL: MyD88-driven Mincle induction is required for MCL to reach the cell surface.\",\n      \"method\": \"Western blotting, flow cytometry, co-immunoprecipitation (heterodimer), MyD88-deficient cells, gene expression analysis\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and genetic (MyD88-KO) epistasis in single lab, two orthogonal methods\",\n      \"pmids\": [\"27005451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Dectin-3 (CLEC4D) is not required for protection against Cryptococcus neoformans infection in a murine pulmonary model. Dectin-3-deficient mice showed no increased susceptibility, no differences in pulmonary leukocyte recruitment or cytokine production, and no defects in uptake or anti-cryptococcal activity of dendritic cells or macrophages — a negative mechanistic finding for this specific pathogen.\",\n      \"method\": \"Clec4d knockout mouse C. neoformans infection model, CFU measurement, flow cytometry, phagocytosis assay, cytokine measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple readouts, single lab; finding is a defined negative result for this pathogen context\",\n      \"pmids\": [\"28107361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Clec4d (CLEC4D/MCL) plays a protective role in resolution of Gram-negative (Klebsiella pneumoniae) pneumonia. Clec4d-/- mice showed progressive bacterial burden and hyperinflammatory sepsis response, with massive neutrophil accumulation in lungs, while WT mice resolved infection. Clec4d-/- neutrophils did not exhibit a defect in bacterial clearance per se, suggesting Clec4d facilitates neutrophil turnover/resolution rather than direct bactericidal activity.\",\n      \"method\": \"Clec4d knockout mouse K. pneumoniae pneumonia model, bacterial burden measurement, lung histology, flow cytometry for neutrophil accumulation, in vitro bacterial killing assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype and mechanistic dissection (killing assay negative), single lab\",\n      \"pmids\": [\"23709686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLEC4D (Dectin-3/MCL/CLECSF8) is a myeloid cell-expressed C-type lectin receptor that recognizes fungal α-mannans and mycobacterial trehalose dimycolate; it constitutively forms heterodimers with Mincle via its stalk region to promote Mincle surface expression and amplify signaling, requires FcRγ and Mincle for its own surface translocation (via a MyD88-driven two-step mechanism), and signals through Syk kinase in myeloid cells to drive phagocytosis, cytokine production, and NF-κB activation, with in vivo roles established in anti-fungal (C. albicans) and anti-mycobacterial (M. tuberculosis) immunity and in resolution of Gram-negative pneumonia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLEC4D (CLECSF8/Dectin-3/MCL) is a myeloid-expressed type II transmembrane C-type lectin receptor that functions as a pattern-recognition and phagocytic receptor in antimicrobial innate immunity [#0, #3]. It is displayed on neutrophils and monocytes and lost upon their differentiation into dendritic cells or macrophages, and its C-type lectin domain mediates ligand recognition and, in non-myeloid contexts, intracellular retention [#1]. CLEC4D recognizes α-mannans on Candida albicans hyphae and drives NF-κB activation, and despite lacking a cytoplasmic signaling motif it triggers Syk-dependent phagocytosis, proinflammatory cytokine production, and the respiratory burst [#1, #2]. Its activity is organized through obligate partnership with Mincle: CLEC4D binds Mincle via its stalk region—four hydrophobic residues are required—to post-translationally stabilize and promote Mincle surface expression, and CLEC4D itself depends on FcRγ and Mincle for surface translocation through a two-step mechanism in which MyD88-driven microbial induction of Mincle licenses the CLEC4D/Mincle heterodimer to exit intracellular stores to the cell surface [#5, #6, #7]. In vivo, CLEC4D is non-redundant for control of C. albicans and Mycobacterium tuberculosis infection and for resolution of Klebsiella pneumoniae pneumonia, where it governs neutrophil turnover rather than direct bacterial killing, but it is dispensable against Cryptococcus neoformans, defining pathogen-specific functional boundaries [#2, #3, #8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established CLEC4D as a monocyte/macrophage-restricted cell-surface glycoprotein capable of internalization, framing it as a candidate endocytic immune receptor before any ligand was known.\",\n      \"evidence\": \"Molecular cloning, Western blot, and cross-linking/internalization assay in transfected cells\",\n      \"pmids\": [\"14971047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand identified\", \"No signaling pathway or adaptor defined\", \"Endocytic function inferred from cross-linking, not physiological ligand\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how a receptor lacking a cytoplasmic signaling motif transmits signals, showing CLEC4D activates Syk to drive phagocytosis, cytokine production, and respiratory burst while not using known adaptors, implying a novel adaptor partner.\",\n      \"evidence\": \"Flow cytometry, reciprocal Co-IP excluding DAP10/DAP12/FcRγ, reporter and functional assays, oligosaccharide microarrays in myeloid cells\",\n      \"pmids\": [\"22689578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The adaptor coupling CLEC4D to Syk was not identified\", \"Physiological ligand not defined here\", \"Mechanism of Syk recruitment unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified CLEC4D as an α-mannan receptor that heterodimerizes with Dectin-2 for enhanced ligand binding and NF-κB-driven inflammation, and demonstrated non-redundant in vivo roles spanning antifungal, antimycobacterial, and Gram-negative pneumonia resolution.\",\n      \"evidence\": \"Reciprocal Co-IP, NF-κB reporter and ligand-binding assays, Clec4d knockout mouse infection models (C. albicans, M. tuberculosis, K. pneumoniae)\",\n      \"pmids\": [\"23911656\", \"25674984\", \"23709686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Dectin-2 and Mincle partnerships are distinct or overlapping was not reconciled\", \"Mechanism of neutrophil resolution in pneumonia not molecularly defined\", \"Phagocytosis vs signaling contributions not separated in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the protective antifungal role to mucosal immunity, showing CLEC4D supports macrophage phagocytosis, killing, NF-κB activation, and tissue-repair signaling that constrains commensal fungal overgrowth in colitis.\",\n      \"evidence\": \"Clec4d knockout DSS-colitis model, fungal burden, macrophage phagocytosis/killing assays, NF-κB reporter, conditioned-media tissue repair assay\",\n      \"pmids\": [\"27280399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-repair effector(s) in conditioned media not identified\", \"Direct receptor-ligand engagement with C. tropicalis not structurally defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the molecular basis of the CLEC4D–Mincle partnership, mapping a stalk-region interaction (four hydrophobic residues) that post-translationally promotes Mincle surface expression and is required for TDM responses.\",\n      \"evidence\": \"Co-IP, surface flow cytometry, Western blot, MCL transgenic/knockout BMDCs, MCL-4S domain mutagenesis with functional rescue\",\n      \"pmids\": [\"25888641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the stalk interface not resolved\", \"How heterodimer stabilization translates to enhanced signaling not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that CLEC4D surface expression itself depends on FcRγ and Mincle and that CLEC4D and Mincle are interdependently co-regulated and microbially induced during infection.\",\n      \"evidence\": \"Monoclonal antibody flow cytometry, Co-IP for FcRγ/Mincle, in vivo BCG infection, TLR-agonist stimulation assays\",\n      \"pmids\": [\"26558717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of FcRγ requirement for surface delivery not detailed\", \"Distinction between Mincle and Dectin-2 partnerships not reconciled\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Integrated the regulatory logic into a two-step model in which MyD88-driven Mincle induction licenses constitutively expressed CLEC4D to exit intracellular stores as a CLEC4D/Mincle heterodimer to the surface.\",\n      \"evidence\": \"Western blot, flow cytometry, Co-IP, MyD88-deficient cells, gene expression epistasis\",\n      \"pmids\": [\"27005451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking machinery mediating co-translocation not identified\", \"Single-lab epistasis without orthogonal confirmation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Delimited the receptor's protective scope by showing CLEC4D is dispensable for control of Cryptococcus neoformans, indicating pathogen-specific rather than universal antimicrobial function.\",\n      \"evidence\": \"Clec4d knockout C. neoformans pulmonary infection, CFU, flow cytometry, phagocytosis and cytokine assays\",\n      \"pmids\": [\"28107361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not exclude redundancy with other receptors for this pathogen\", \"Negative result limited to the murine pulmonary context tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CLEC4D heterodimerization and its quantitative contribution to signaling versus phagocytosis in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CLEC4D alone or in heterodimer\", \"Trafficking machinery for surface delivery unknown\", \"Effectors mediating tissue repair and neutrophil resolution unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"CLEC4D/Mincle heterodimer\",\n      \"CLEC4D/Dectin-2 heterodimer\"\n    ],\n    \"partners\": [\n      \"CLEC4E\",\n      \"CLEC6A\",\n      \"FCER1G\",\n      \"SYK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}