CLEC10A explained

C-type lectin domain family 10 member A (CLEC10A) also designated as CD301 is a protein that in humans is encoded by the CLEC10A gene.[1] CLEC10A is part of the C-type lectin superfamily and binds to N-Acetylgalactosamine (GalNAc). It is mainly expressed on myeloid cells and also on oocytes and very early stages of embryogenesis. CLEC10A is used as a marker of the CD1c+ dendritic cell subgroup, also called cDC2.[2] The actions of CLEC10A are diverse, depending on the ligand and environment.[3]

Function

Generally, C-type lectins bind carbohydrate moieties usually in the presence of Ca2+ and have diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response.[4]

CLEC10A is a type II transmembrane protein (passing one time through the membrane and oriented with the N terminus inward) that induces endocytosis after ligand binding. To release the ligand in the endosome, participating Ca2+ ions have to be unbound first. This leads to a significant increase in cytoplasmic Ca2+ concentration.

CLEC10A binds most strongly to N-Acetylgalactosamine (GalNAc), preferring α-GalNAc over β-GalNAc, unmodified galactose is bound very weakly. CLEC10A is the only C-type lectin within the human immune system that exclusively recognizes terminal GalNAc.[5] This includes the Tn antigen (GalNAc O-bound to serine or threonine) which is prominently expressed on carcinomas, where it can also be sialylated. These tumor-associated antigens (Neu5Acα2,6-Tn, and NeuGcα2,6-Tn) are also bound.[6]

CLEC10A has also been shown to bind GalNAc in the teichoic acid of the Staphylococcus aureus cell wall and the surface of parasites.[7] [8]

CLEC10A is expressed by dendritic cells that differentiate from monocytes recruited to inflammatory environments.[9]

CD45 contains a Tn antigen in exon B. CD45 has 3 important exons (4,5,6), that are designated A,B,C. Isoforms of CD45 are labeled depending on the presence of these exons. CLEC10A can for example bind CD45RB or CD45R, which is shorthand for CD45RABC. Binding causes attenuation of T cell activity, apoptosis, and immunosuppression. However, active T cells express shorter isoforms of CD45 (CD45RO, CD45RA) that lack exon B.

CLEC10A signalling induces IL-10 production in dendritic cells, in part through increasing intracellular Ca2+ concentration. IL-10 is the main regulatory and anti-inflammatory cytokine produced in humans. In contrast, low concentrations of intracellular Ca2+ result in production of IL-12, a pro-inflammatory cytokine that also leads to Th1 polarisation.

In cancer research, CLEC10A expression was found to both improve[10] [11] [12] and worsen[13] survival.

In animal models, deficiency of the orthologue to CLEC10A, Mgl1 is associated with worse outcomes in infection and excessive inflammation.[14]

Further reading

Notes and References

  1. Suzuki N, Yamamoto K, Toyoshima S, Osawa T, Irimura T . Molecular cloning and expression of cDNA encoding human macrophage C-type lectin. Its unique carbohydrate binding specificity for Tn antigen . Journal of Immunology . 156 . 1 . 128–135 . January 1996 . 10.4049/jimmunol.156.1.128 . 8598452 . 25597354 . free .
  2. Heger L, Balk S, Lühr JJ, Heidkamp GF, Lehmann CH, Hatscher L, Purbojo A, Hartmann A, Garcia-Martin F, Nishimura SI, Cesnjevar R, Nimmerjahn F, Dudziak D . 6 . CLEC10A Is a Specific Marker for Human CD1c+ Dendritic Cells and Enhances Their Toll-Like Receptor 7/8-Induced Cytokine Secretion . Frontiers in Immunology . 9 . 744 . 2018-04-27 . 29755453 . 5934495 . 10.3389/fimmu.2018.00744 . free .
  3. Hoober JK . ASGR1 and Its Enigmatic Relative, CLEC10A . International Journal of Molecular Sciences . 21 . 14 . 4818 . July 2020 . 32650396 . 7404283 . 10.3390/ijms21144818 . free .
  4. Zelensky AN, Gready JE . The C-type lectin-like domain superfamily . The FEBS Journal . 272 . 24 . 6179–6217 . December 2005 . 16336259 . 10.1111/j.1742-4658.2005.05031.x . 7084402 .
  5. van Kooyk Y, Ilarregui JM, van Vliet SJ . Novel insights into the immunomodulatory role of the dendritic cell and macrophage-expressed C-type lectin MGL . Immunobiology . 220 . 2 . 185–192 . February 2015 . 25454488 . 10.1016/j.imbio.2014.10.002 . 32172457 . free .
  6. Mortezai N, Behnken HN, Kurze AK, Ludewig P, Buck F, Meyer B, Wagener C . Tumor-associated Neu5Ac-Tn and Neu5Gc-Tn antigens bind to C-type lectin CLEC10A (CD301, MGL) . Glycobiology . 23 . 7 . 844–852 . July 2013 . 23507963 . 10.1093/glycob/cwt021 .
  7. Mnich ME, van Dalen R, Gerlach D, Hendriks A, Xia G, Peschel A, van Strijp JA, van Sorge NM . 6 . The C-type lectin receptor MGL senses N-acetylgalactosamine on the unique Staphylococcus aureus ST395 wall teichoic acid . Cellular Microbiology . 21 . 10 . e13072 . October 2019 . 31219660 . 6771913 . 10.1111/cmi.13072 .
  8. van Vliet SJ, van Liempt E, Saeland E, Aarnoudse CA, Appelmelk B, Irimura T, Geijtenbeek TB, Blixt O, Alvarez R, van Die I, van Kooyk Y . 6 . Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells . International Immunology . 17 . 5 . 661–669 . May 2005 . 15802303 . 10.1093/intimm/dxh246 .
  9. Tang-Huau TL, Gueguen P, Goudot C, Durand M, Bohec M, Baulande S, Pasquier B, Amigorena S, Segura E . 6 . Human in vivo-generated monocyte-derived dendritic cells and macrophages cross-present antigens through a vacuolar pathway . Nature Communications . 9 . 1 . 2570 . July 2018 . 29967419 . 10.1038/s41467-018-04985-0 . 6028641 . 2018NatCo...9.2570T .
  10. Kurze AK, Buhs S, Eggert D, Oliveira-Ferrer L, Müller V, Niendorf A, Wagener C, Nollau P . 6 . Immature O-glycans recognized by the macrophage glycoreceptor CLEC10A (MGL) are induced by 4-hydroxy-tamoxifen, oxidative stress and DNA-damage in breast cancer cells . Cell Communication and Signaling . 17 . 1 . 107 . August 2019 . 31455323 . 6712659 . 10.1186/s12964-019-0420-9 . free .
  11. Eggink LL, Roby KF, Cote R, Kenneth Hoober J . An innovative immunotherapeutic strategy for ovarian cancer: CLEC10A and glycomimetic peptides . Journal for Immunotherapy of Cancer . 6 . 1 . 28 . April 2018 . 29665849 . 5905120 . 10.1186/s40425-018-0339-5 . free .
  12. Qin Y, Wang L, Zhang L, Li J, Liao L, Huang L, Li W, Yang J . 6 . Immunological role and prognostic potential of CLEC10A in pan-cancer . American Journal of Translational Research . 14 . 5 . 2844–2860 . 2021 . 35702069 . 10.2139/ssrn.3932103 . 9185031 . 242193292 .
  13. Dusoswa SA, Verhoeff J, Abels E, Méndez-Huergo SP, Croci DO, Kuijper LH, de Miguel E, Wouters VM, Best MG, Rodriguez E, Cornelissen LA, van Vliet SJ, Wesseling P, Breakefield XO, Noske DP, Würdinger T, Broekman ML, Rabinovich GA, van Kooyk Y, Garcia-Vallejo JJ . 6 . Glioblastomas exploit truncated O-linked glycans for local and distant immune modulation via the macrophage galactose-type lectin . Proceedings of the National Academy of Sciences of the United States of America . 117 . 7 . 3693–3703 . February 2020 . 32019882 . 7035608 . 10.1073/pnas.1907921117 . 2020PNAS..117.3693D . free .
  14. Jondle CN, Sharma A, Simonson TJ, Larson B, Mishra BB, Sharma J . Macrophage Galactose-Type Lectin-1 Deficiency Is Associated with Increased Neutrophilia and Hyperinflammation in Gram-Negative Pneumonia . Journal of Immunology . 196 . 7 . 3088–3096 . April 2016 . 26912318 . 4936400 . 10.4049/jimmunol.1501790 .

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