Biology:NCR3

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene.[1][2][3] NCR3 has also been designated as CD337 (cluster of differentiation 337) and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44).[4]

Identification

NKp30 receptor was first identified in 1999. According to Western blot analysis specific monoclonal antibodies reacted with 30kDa molecule, therefore was the protein named NKp30.[5]

Structure

Gene for NKp30 is located in the MHC class III region of the human MHC locus and encodes 190 amino acid long type I transmembrane receptor which belongs to immunoglobulin super family (IgSF).[5][6] NKp30 has a mass of 30 kDa and includes one Ig-like extracellular domain which is 138 amino acids long, a 19 amino acid transmembrane (TM) domain and a 33 amino acid cytoplasmic tail.[5][4][7] The Ig-like domain consists of 2 antiparallel beta-sheets linked by a disulphide bond.[7][8] The extracellular domain contains two potential sites for N-linked glycosylation involved in ligand binding.[5] The TM domain contains a positivelly charged arginine residue, which associates with negatively charged aspartate in TM domain of ITAM adaptor molecules CD3ζ and FCεRIγ. This is a common feature of other NK cell activating receptors as well.[5][7][9] Accordingly the cytoplasmic tail lacks typical ITAM consensus sequence.

Splicing variants

We can find six different splicing variants on the cell surface. NKp30a, NKp30b and NKp30c encode molecules with extracellular V-type Ig domain. NKp30d, NKp30e and NKp30f encode extracellular C-type Ig domain. Splicing variants also differ in their cytosolic intracellular domains depending on the translation of variants of exon 4 (NKp30a,b or c).[4][6]

The distribution of splicing variants of NKp30 varies in tissues and results in different NK cell responses. NKp30a/b engagement stimulates the release of high amounts of IFN-γ, whereas activation of NKp30c induces IL-10 production and only small amounts of IFN-γ. First two are therefore considered as immunostimulatory isoforms which enhance Th1 immune response, while NKp30c mediates immunosuppressive signaling most likely because of reduced association with CD3ζ adaptor after cross-linking with ligand.[6]

Gastrointestinal stromal tumor patients who express NKp30c isoform have worse prognosis compared with patients expressing other isoforms, mainly as a consequence of NK cell immunosuppressive character.[6][10]

Expression

NCR3 is expressed mainly on cytoplasmic membrane of mature NK cells and functions as an activating receptor of NK cells. However it is also expressed on surface of CD8+ T cells, γδ T cells with Vδ1 TCR and ILC2.[4][9] The presence of IL-15 stimulates the expression of NKp30+ CD8+ T cells with anti-tumor activity.[4][11] Expression of NKp30 in γδ T cells is induced by IL-2 or IL-15.[4][12] After progesteron stimulation NKp30 can be found on the cytoplasmic membrane of endometrial epithelial cells as well.[6]

Function

NKp30 plays a major role in NK anti-tumor response and immunosurveillance, mainly by activating NK cell cytotoxicity and cytokine secretion.[4][13] Direct killing happens similarly to other natural cytotoxicity receptors (NCRs) such as NKp44 and NKp46.[5][14] NCR3 has a wide range of non-MHC ligands secreted or expressed by cancer or virus-infected cells, e.g. to heparan sulfate glycosaminoglycans (HS GAGs) and B7-H6.[4][7][15][13]

Heparan sulfate epitopes are in healthy tissue as well as on tumor cells, where HS GAGs are changed or differ in ligands (HMGB1, S100A8/A9) in contrast to healthy tissue. In addition, interaction of NCR with HS GAGs can facilitate binding to other cellular ligands. Thus via heparan sulfate epitopes NCRs can bind to the same ligands and exert similar reactions and at the same time also have their own unique interacting partners. It is also known that heparan sulfate epitopes lead to better signaling through growth factor receptors, NCRs could be thus evolved to recognize unusual HS GAGs on malignant cells as transformed cell patterns.[13]

Ligation of NKp30 and intracellular protein HLA-B-associated transcript 3 (BAT3) released by tumour cells to extracellular matrix results in NK and dendritic cell cross-talk.[4][15][8]

Human cytomegalovirus protein pp65 is another ligand of NKp30. The ligation leads to disruption of the interaction between NKp30 and CD3ζ and thus decreases the activation of NK cells and its cytotoxicity. This is a mechanism of HMCV to evade NK cell surveillance.[6][7][15]

Patients with primary Sjögren's syndrome express higher levels of NKp30+ NK cells (and its ligation with B7-H6 expressed in salivary glands) in comparison to healthy controls.[4]

NKp30 and dendritic cells

Immature dendritic cells can be lysed upon stimulation of NKp30 on NK cells.[6] Accordingly. patients with acute myeloid leukemia (AML), who often show downregulation in NKp30 expression, were incapable of effectively lysing both autologous and allogeneic immature dendritic cells. The ability of NK cells to kill immature dendritic cells may serve to check the quality of dendritic cell maturation process.[14] Interestingly at the same time immunostimulatory capacity of dendritic cells can be enhanced via interaction with NKp30 with ligands expressed on immature dendritic cells.[6] Upon such stimulation NK cells produce TNFα which is capable of inducing dendritic cell maturation.[14]

NCR3 during pregnancy

Uterine NK cells (uNK) are the most abundant lymphocyte population in uterus during pregnancy on the maternal-fetal interface. These cells are responsible for angiogenesis and vascular remodelling in trophoblast.[16][17] uNK cells express NKp30 and its ligands are expressed by trophoblast cells. Though these ligands have not yet been identified, this interaction has a potential to regulate fetal-maternal interface.[18][4] The uNK cells dominantly express the inhibitory NKp30c isoform.[19]

References

  1. ↑ "Genes in a 220-kb region spanning the TNF cluster in human MHC". Genomics 31 (2): 215–22. January 1996. doi:10.1006/geno.1996.0034. PMID 8824804. 
  2. ↑ "Identification of novel single nucleotide substitutions in the NKp30 gene expressed in human natural killer cells". Tissue Antigens 58 (4): 255–8. October 2001. doi:10.1034/j.1399-0039.2001.580406.x. PMID 11782277. 
  3. ↑ "Entrez Gene: NCR3 natural cytotoxicity triggering receptor 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=259197. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 "The Natural Cytotoxicity Receptors in Health and Disease". Frontiers in Immunology 10: 909. 2019-05-07. doi:10.3389/fimmu.2019.00909. PMID 31134055. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells". The Journal of Experimental Medicine 190 (10): 1505–16. November 1999. doi:10.1084/jem.190.10.1505. PMID 10562324. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Natural cytotoxicity receptors and their ligands". Immunology and Cell Biology 92 (3): 221–9. March 2014. doi:10.1038/icb.2013.98. PMID 24366519. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "NKp30 - A prospective target for new cancer immunotherapy strategies". British Journal of Pharmacology 177 (20): 4563–4580. October 2020. doi:10.1111/bph.15222. PMID 32737988. 
  8. ↑ 8.0 8.1 "Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression". Frontiers in Immunology 8: 369. 2017-03-30. doi:10.3389/fimmu.2017.00369. PMID 28424697. 
  9. ↑ 9.0 9.1 "B7-H6/NKp30 interaction: a mechanism of alerting NK cells against tumors". Cellular and Molecular Life Sciences 68 (21): 3531–9. November 2011. doi:10.1007/s00018-011-0802-7. PMID 21877119. 
  10. ↑ "Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors". Nature Medicine 17 (6): 700–7. June 2011. doi:10.1038/nm.2366. PMID 21552268. 
  11. ↑ "Distinct human circulating NKp30+FcεRIγ+CD8+ T cell population exhibiting high natural killer-like antitumor potential". Proceedings of the National Academy of Sciences of the United States of America 115 (26): E5980–E5989. June 2018. doi:10.1073/pnas.1720564115. PMID 29895693. Bibcode: 2018PNAS..115E5980C. 
  12. ↑ "Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells". Blood 118 (4): 992–1001. July 2011. doi:10.1182/blood-2011-02-339135. PMID 21633088. 
  13. ↑ 13.0 13.1 13.2 "Natural cytotoxicity receptors: pattern recognition and involvement of carbohydrates". TheScientificWorldJournal 5: 151–4. February 2005. doi:10.1100/tsw.2005.22. PMID 15759080. 
  14. ↑ 14.0 14.1 14.2 "Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis". Annual Review of Immunology 19 (1): 197–223. April 2001. doi:10.1146/annurev.immunol.19.1.197. PMID 11244035. 
  15. ↑ 15.0 15.1 15.2 "Virus-mediated inhibition of natural cytotoxicity receptor recognition". Cellular and Molecular Life Sciences 69 (23): 3911–20. December 2012. doi:10.1007/s00018-012-1001-x. PMID 22547090. 
  16. ↑ "Uterine Natural Killer Cells". Frontiers in Immunology 10: 960. 2019-05-01. doi:10.3389/fimmu.2019.00960. PMID 31118936. 
  17. ↑ "Uterine NK cells: active regulators at the maternal-fetal interface". The Journal of Clinical Investigation 124 (5): 1872–9. May 2014. doi:10.1172/JCI68107. PMID 24789879. 
  18. ↑ "Decidual NK cells regulate key developmental processes at the human fetal-maternal interface". Nature Medicine 12 (9): 1065–74. September 2006. doi:10.1038/nm1452. PMID 16892062. 
  19. ↑ "Natural cytotoxicity receptor splice variants orchestrate the distinct functions of human natural killer cell subtypes". Nature Communications 6 (1): 10183. December 2015. doi:10.1038/ncomms10183. PMID 26666685. Bibcode: 2015NatCo...610183S. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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