Affinage

CLEC4D

C-type lectin domain family 4 member D · UniProt Q8WXI8

Length
215 aa
Mass
24.7 kDa
Annotated
2026-04-28
100 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLEC4D is a monocyte/macrophage-restricted type II transmembrane C-type lectin receptor that functions as an endocytic pattern recognition receptor mediating phagocytosis and innate immune signaling against bacterial and fungal pathogens. It is a 215-amino acid glycoprotein with a single carbohydrate recognition domain that undergoes rapid internalization upon cross-linking and directly recognizes microbial ligands including fungal glucuronoxylomannan, activating NF-κB and ERK signaling via the CARD9 adaptor to drive pro-inflammatory cytokine production (PMID:14971047, PMID:30131805). Clec4d-deficient mice display increased susceptibility to Klebsiella pneumoniae sepsis, Mycobacterium tuberculosis infection, and Cryptococcus pulmonary infection, with exacerbated neutrophil accumulation and impaired pathogen clearance, indicating a non-redundant role in both pathogen uptake and resolution of pulmonary inflammation (PMID:23709686, PMID:25674984, PMID:30131805). A human CLEC4D polymorphism is associated with increased susceptibility to pulmonary tuberculosis (PMID:25674984).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2004 Medium

    The molecular identity and basic receptor behavior of CLEC4D were established, revealing it as a monocyte/macrophage-restricted endocytic receptor with a single CRD but no cytoplasmic signaling motifs, raising the question of how it signals and what ligands it recognizes.

    Evidence cDNA cloning, biochemical characterization in transfected cells, cross-linking/internalization assay

    PMID:14971047

    Open questions at the time
    • Natural ligands unidentified
    • Signaling mechanism unknown given absence of cytoplasmic signaling motifs
    • In vivo function not tested
  2. 2013 Medium

    Clec4d was shown to be non-redundantly required for resolution of Gram-negative pneumonic sepsis in vivo, but the mechanism was not direct bacterial killing — instead Clec4d facilitates neutrophil turnover at inflammatory sites, establishing a role in inflammation resolution rather than just pathogen recognition.

    Evidence Clec4d knockout mouse Klebsiella pneumoniae infection model with bacterial burden quantification, histopathology, and neutrophil functional assays

    PMID:23709686

    Open questions at the time
    • Single-lab KO study; mechanism of neutrophil turnover regulation not defined
    • Direct ligand on Klebsiella not identified
    • Signaling pathway downstream of Clec4d in this context unknown
  3. 2015 High

    CLEC4D was established as a phagocytic receptor for mycobacteria: knockout mice had higher M. tuberculosis burdens and mortality, and the phagocytic defect was rescued by opsonization, directly linking CLEC4D to mycobacterial uptake. A human genetic association further connected CLEC4D to tuberculosis susceptibility.

    Evidence Clecsf8 knockout mouse M. tuberculosis infection, bacterial burden measurement, flow cytometry, opsonization rescue, human genetic association study

    PMID:25674984

    Open questions at the time
    • Specific mycobacterial ligand for CLEC4D not identified
    • Human genetic association is correlative; causal mechanism in humans not proven
    • How CLEC4D signals without cytoplasmic signaling motifs during phagocytosis not resolved
  4. 2018 High

    The signaling question was resolved: CLEC4D directly binds fungal glucuronoxylomannan and activates NF-κB and ERK via the CARD9 adaptor, connecting receptor engagement to pro-inflammatory cytokine production and establishing the CLEC4D–CARD9 axis as essential for anti-cryptococcal immunity.

    Evidence Direct binding assay, NF-κB/ERK reporter assays, Dectin-3 and CARD9 knockout mouse Cryptococcus infection model, cytokine measurement, alveolar macrophage functional assays

    PMID:30131805

    Open questions at the time
    • How CLEC4D couples to CARD9 without cytoplasmic signaling motifs (likely via an associated signaling chain such as FcRγ) not molecularly defined in these studies
    • Structural basis of GXM recognition by the CRD not determined
    • Whether the CARD9-dependent pathway also operates during antibacterial responses not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which CLEC4D, which lacks cytoplasmic signaling motifs, couples to the CARD9 signaling cascade remains undefined, and the specific microbial ligands recognized during bacterial (Klebsiella, M. tuberculosis) infections have not been identified.
  • Transmembrane signaling partner (e.g., FcRγ chain association) not biochemically validated
  • No structural model for CLEC4D–ligand interaction
  • Contribution to human disease beyond tuberculosis association not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 3
Partners
CARD9

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Human CLECSF8 (CLEC4D) is a type II membrane glycoprotein of 215 amino acids with a single carbohydrate recognition domain (CRD) and no consensus signaling motifs in its cytoplasmic tail. It is expressed in a monocyte/macrophage-restricted pattern, and cross-linking of the receptor leads to rapid internalization, identifying it as an endocytic receptor. cDNA cloning, biochemical characterization of transfected cells, cross-linking/internalization assay European Journal of Immunology Medium 14971047
2013 Clec4d plays a non-redundant role in resolution of Gram-negative (Klebsiella pneumoniae) pneumonic sepsis: Clec4d-/- mice show progressive bacteremia, hyperinflammatory sepsis, and massive neutrophil accumulation in lungs, but Clec4d-/- neutrophils have no intrinsic defect in bacterial killing, suggesting Clec4d facilitates neutrophil turnover/resolution of inflammation rather than direct bactericidal activity. Clec4d knockout mouse infection model, bacterial burden quantification, histopathology, neutrophil functional assays Journal of Leukocyte Biology Medium 23709686
2015 CLECSF8 (CLEC4D/MCL) is required for anti-mycobacterial host defense: Clecsf8-/- mice exhibit higher M. tuberculosis burdens, increased mortality, exacerbated pulmonary neutrophil recruitment, and reduced mycobacterial uptake by pulmonary leukocytes. Opsonization of bacteria rescued the phagocytic defect and reduced bacterial burdens, indicating CLEC4D mediates mycobacterial phagocytosis. A human CLECSF8 polymorphism associates with increased susceptibility to pulmonary tuberculosis. Clecsf8 knockout mouse M. tuberculosis infection model, bacterial burden measurement, flow cytometry of leukocyte populations, opsonization rescue experiment, human genetic association Cell Host & Microbe High 25674984
2018 Dectin-3 (the mouse ortholog of CLEC4D, encoded by Clec4d) directly recognizes glucuronoxylomannan (GXM) from Cryptococcus neoformans serotype AD and C. gattii serotype B, activating NF-κB and ERK signaling pathways to induce pro-inflammatory cytokine production. Dectin-3- and CARD9-deficient mice are highly susceptible to pulmonary C.n-AD and C.g-B infection, with impaired alveolar macrophage accumulation and killing, and cytokine induction by these GXMs was abolished by Dectin-3 or CARD9 deficiency. Direct binding assay (Dectin-3 as GXM receptor), NF-κB/ERK reporter assays, Dectin-3 and CARD9 knockout mouse infection model, cytokine measurement, alveolar macrophage functional assays Frontiers in Immunology High 30131805

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 676 14668867
2007 Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proceedings of the National Academy of Sciences of the United States of America 551 18040043
2010 Mcl-1; the molecular regulation of protein function. FEBS letters 451 20540941
2010 The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nature chemical biology 337 20562877
2003 DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Genes & development 271 14633975
2021 Targeting MCL-1 in cancer: current status and perspectives. Journal of hematology & oncology 239 33883020
2005 Mcl-1. The international journal of biochemistry & cell biology 208 15474972
2012 Delving deeper: MCL-1's contributions to normal and cancer biology. Trends in cell biology 190 23026029
2010 Mcl-1 is essential for germinal center formation and B cell memory. Science (New York, N.Y.) 189 20929728
2020 Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood reviews 168 32204955
2008 Unique biology of Mcl-1: therapeutic opportunities in cancer. Current molecular medicine 164 18336294
2006 Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis. The Journal of biological chemistry 157 16478725
2014 Mcl-1 ubiquitination: unique regulation of an essential survival protein. Cells 156 24814761
2003 Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. Blood 130 12637318
2002 Direct repression of the Mcl-1 promoter by E2F1. Oncogene 126 11857079
2020 Saga of Mcl-1: regulation from transcription to degradation. Cell death and differentiation 125 31907390
2004 Mcl-1 regulation and its role in multiple myeloma. Cell cycle (Georgetown, Tex.) 120 15467463
2018 Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia. Journal of medicinal chemistry 114 29641204
2007 A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. Oncogene 107 17653083
2018 MCL-1 inhibition in cancer treatment. OncoTargets and therapy 106 30425521
2010 Ubiquitin-independent degradation of antiapoptotic MCL-1. Molecular and cellular biology 106 20385764
2023 MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction. Redox biology 103 38100883
2022 Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nature communications 94 35449130
2006 Mcl-1: a highly regulated cell death and survival controller. Journal of biomedical science 90 16456709
2017 Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL. Blood advances 89 29034364
2015 The C-type lectin receptor CLECSF8/CLEC4D is a key component of anti-mycobacterial immunity. Cell host & microbe 88 25674984
2004 Regulation of neutrophil apoptosis by Mcl-1. Biochemical Society transactions 85 15157168
2020 Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor. Journal of medicinal chemistry 82 33146521
2019 Multiple myeloma with 1q21 amplification is highly sensitive to MCL-1 targeting. Blood advances 79 31856269
2013 MiR-139 inhibits Mcl-1 expression and potentiates TMZ-induced apoptosis in glioma. CNS neuroscience & therapeutics 78 23551751
2012 Regulation of Mcl-1 by SRSF1 and SRSF5 in cancer cells. PloS one 78 23284704
2012 Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons. Cell death and differentiation 77 22976837
2019 Molecular Comprehension of Mcl-1: From Gene Structure to Cancer Therapy. Trends in cell biology 76 31030977
2004 The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. European journal of immunology 76 15459900
2011 Mcl-1 ubiquitination and destruction. Oncotarget 73 21608150
2011 Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition. Blood 73 22128141
2011 Regulation of neutrophil survival/apoptosis by Mcl-1. TheScientificWorldJournal 72 22125448
2004 The human C-type lectin CLECSF8 is a novel monocyte/macrophage endocytic receptor. European journal of immunology 69 14971047
2020 Development of Mcl-1 inhibitors for cancer therapy. European journal of medicinal chemistry 62 33333396
2016 Mcl-1 dynamics influence mitotic slippage and death in mitosis. Oncotarget 62 26769847
2014 Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis. Cell death and differentiation 62 24769731
2003 Transcriptional and translational control of Mcl-1 during apoptosis. Archives of biochemistry and biophysics 62 12941295
2020 Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer. Theranostics 60 32724460
2006 Regulation of Mcl-1 expression in rheumatoid arthritis synovial macrophages. Arthritis and rheumatism 60 17009247
2017 FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors. Molecular cancer therapeutics 58 28619760
2019 Hot-Spots of Mcl-1 Protein. Journal of medicinal chemistry 57 31580668
2016 Dual modulation of MCL-1 and mTOR determines the response to sunitinib. The Journal of clinical investigation 56 27893461
2017 Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy. The Journal of clinical investigation 54 29227281
2023 Targeting MCL-1 protein to treat cancer: opportunities and challenges. Frontiers in oncology 53 37601693
2016 Allosteric inhibition of antiapoptotic MCL-1. Nature structural & molecular biology 51 27159560
2016 BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells. Oncotarget 51 27351224
2013 C-type lectin receptor Clec4d plays a protective role in resolution of Gram-negative pneumonia. Journal of leukocyte biology 51 23709686
2020 AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 48 31937611
2020 Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL. Blood advances 47 32191807
2015 Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450. Cell death & disease 46 26068790
2016 Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors. ACS medicinal chemistry letters 44 28197319
2014 Bak and Mcl-1 are essential for Temozolomide induced cell death in human glioma. Oncotarget 44 24811082
2013 Caloric restriction modulates Mcl-1 expression and sensitizes lymphomas to BH3 mimetic in mice. Blood 44 23966420
2021 The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer. Oncogene 43 33627786
2018 SOX11 augments BCR signaling to drive MCL-like tumor development. Blood 43 29615403
2011 Quercetin downregulates Mcl-1 by acting on mRNA stability and protein degradation. British journal of cancer 43 21750559
2022 Skp2 stabilizes Mcl-1 and confers radioresistance in colorectal cancer. Cell death & disease 41 35301297
2005 Mcl-1 blocks radiation-induced apoptosis and inhibits clonogenic cell death. Anticancer research 36 16080514
2016 miR-153 regulates apoptosis and autophagy of cardiomyocytes by targeting Mcl-1. Molecular medicine reports 34 27220418
2016 Survival control of malignant lymphocytes by anti-apoptotic MCL-1. Leukemia 34 27479182
2018 Dectin-3 Recognizes Glucuronoxylomannan of Cryptococcus neoformans Serotype AD and Cryptococcus gattii Serotype B to Initiate Host Defense Against Cryptococcosis. Frontiers in immunology 33 30131805
2017 FBXO4 inhibits lung cancer cell survival by targeting Mcl-1 for degradation. Cancer gene therapy 33 28776569
2018 Coxiella burnetii Inhibits Neutrophil Apoptosis by Exploiting Survival Pathways and Antiapoptotic Protein Mcl-1. Infection and immunity 32 29311244
2020 Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. Blood advances 31 32569380
2013 Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages. Cellular & molecular immunology 29 23872918
2016 Repression of Mcl-1 and disruption of the Mcl-1/Bak interaction in myeloma cells couple ER stress to mitochondrial apoptosis. Cancer letters 27 27697610
2010 Autogenous bone marrow stromal cell sheets-loaded mPCL/TCP scaffolds induced osteogenesis in a porcine model of spinal interbody fusion. Tissue engineering. Part A 26 20973747
2020 Sphingosine kinase-2 is overexpressed in large granular lymphocyte leukaemia and promotes survival through Mcl-1. British journal of haematology 24 32124438
2019 Targeting KPNB1 overcomes TRAIL resistance by regulating DR5, Mcl-1 and FLIP in glioblastoma cells. Cell death & disease 24 30742128
2019 CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax. Molecular pharmacology 24 31467029
2018 Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming. The FEBS journal 24 29775995
2022 Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage. Cells 23 35563775
2015 AML sensitivity to YM155 is modulated through AKT and Mcl-1. Cancer letters 23 26118775
2010 Synergism between p53 and Mcl-1 in protecting from hepatic injury, fibrosis and cancer. Journal of hepatology 23 21146511
2014 STAT3 and MCL-1 associate to cause a mesenchymal epithelial transition. Journal of cell science 22 24481815
2011 Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC cancer 22 21247487
2009 Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR. Medical oncology (Northwood, London, England) 22 19763916
2022 Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance. Cell death & disease 21 36535926
2016 Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma. Cancer biology & therapy 21 27246906
2021 Requirement for antiapoptotic MCL-1 during early erythropoiesis. Blood 20 33512417
2020 Epigenetic modulation of FBW7/Mcl-1 pathway for lung cancer therapy. Cancer biology & therapy 20 33336620
2018 Repurposing of mTOR Complex Inhibitors Attenuates MCL-1 and Sensitizes to PARP Inhibition. Molecular cancer research : MCR 20 30201826
2015 EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma. Cancer biology & therapy 20 25756510
2019 Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL. Bioorganic chemistry 19 31031018
2021 Phosphatase PP2A enhances MCL-1 protein half-life in multiple myeloma cells. Cell death & disease 18 33658484
2019 Photocatalytic proximity labelling of MCL-1 by a BH3 ligand. Communications chemistry 18 33763603
2009 IEX-1-induced cell death requires BIM and is modulated by MCL-1. Biochemical and biophysical research communications 18 19285955
2020 DYRK1A suppression restrains Mcl-1 expression and sensitizes NSCLC cells to Bcl-2 inhibitors. Cancer biology & medicine 17 32587776
2017 BIRC6 mediates imatinib resistance independently of Mcl-1. PloS one 17 28520795
2013 MCL-1ES induces MCL-1L-dependent BAX- and BAK-independent mitochondrial apoptosis. PloS one 17 24260268
2009 Immunotoxin BL22 induces apoptosis in mantle cell lymphoma (MCL) cells dependent on Bcl-2 expression. British journal of haematology 17 19821820
2023 Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation. Haematologica 16 36226498
2020 Design, synthesis and biological evaluation of tyrosine derivatives as Mcl-1 inhibitors. European journal of medicinal chemistry 16 32088497
2017 Toward Understanding Mcl-1 Promiscuous and Specific Binding Mode. Journal of chemical information and modeling 16 29016132
2017 Upregulation of Mcl-1 inhibits JQ1-triggered anticancer activity in hepatocellular carcinoma cells. Biochemical and biophysical research communications 16 29287727