NCR3
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Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene.[3][4][5] 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).[6]
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.[7]
Structure
Gene for NKp30 is located in the
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).[6][8]
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.[8]
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.[8][12]
Expression
NCR3 is expressed mainly on
Function
NKp30 plays a major role in NK anti-tumor response and
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.[15]
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.[6][17][10]
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.[8][9][17]
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.[6]
NKp30 and dendritic cells
Immature dendritic cells can be lysed upon stimulation of NKp30 on NK cells.[8] 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.[16] Interestingly at the same time immunostimulatory capacity of dendritic cells can be enhanced via interaction with NKp30 with ligands expressed on immature dendritic cells.[8] Upon such stimulation NK cells produce TNFα which is capable of inducing dendritic cell maturation.[16]
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.[18][19] 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.[20][6] The uNK cells dominantly express the inhibitory NKp30c isoform.[21]
References
- ^ a b c ENSG00000236979, ENSG00000206430, ENSG00000237808, ENSG00000236315, ENSG00000223833, ENSG00000225211, ENSG00000204475 GRCh38: Ensembl release 89: ENSG00000237103, ENSG00000236979, ENSG00000206430, ENSG00000237808, ENSG00000236315, ENSG00000223833, ENSG00000225211, ENSG00000204475 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8824804.
- PMID 11782277.
- ^ "Entrez Gene: NCR3 natural cytotoxicity triggering receptor 3".
- ^ PMID 31134055.
- ^ PMID 10562324.
- ^ S2CID 38667462.
- ^ PMID 32737988.
- ^ PMID 28424697.
- ^ S2CID 22483622.
- S2CID 22671469.
- PMID 29895693.
- PMID 21633088.
- ^ PMID 15759080.
- ^ PMID 11244035.
- ^ S2CID 16482529.
- PMID 31118936.
- PMID 24789879.
- S2CID 19158471.
- PMID 26666685.
Further reading
- Djeu JY, Jiang K, Wei S (March 2002). "A view to a kill: signals triggering cytotoxicity". Clinical Cancer Research. 8 (3): 636–40. PMID 11895890.
- Holzinger I, de Baey A, Messer G, Kick G, Zwierzina H, Weiss EH (1995). "Cloning and genomic characterization of LST1: a new gene in the human TNF region". Immunogenetics. 42 (5): 315–22. S2CID 19916860.
- de Baey A, Fellerhoff B, Maier S, Martinozzi S, Weidle U, Weiss EH (November 1997). "Complex expression pattern of the TNF region gene LST1 through differential regulation, initiation, and alternative splicing". Genomics. 45 (3): 591–600. PMID 9367684.
- Neville MJ, Campbell RD (April 1999). "A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC". Journal of Immunology. 162 (8): 4745–54. S2CID 46517924.
- Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, et al. (November 1999). "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. PMID 10562324.
- Sivakamasundari R, Raghunathan A, Zhang CY, Chowdhury RR, Weissman SM (July 2000). "Expression and cellular localization of the protein encoded by the 1C7 gene: a recently described component of the MHC". Immunogenetics. 51 (8–9): 723–32. S2CID 27714493.
- Le Bouteiller P, Barakonyi A, Giustiniani J, Lenfant F, Marie-Cardine A, Aguerre-Girr M, et al. (December 2002). "Engagement of CD160 receptor by HLA-C is a triggering mechanism used by circulating natural killer (NK) cells to mediate cytotoxicity". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16963–8. PMID 12486241.
- Augugliaro R, Parolini S, Castriconi R, Marcenaro E, Cantoni C, Nanni M, et al. (May 2003). "Selective cross-talk among natural cytotoxicity receptors in human natural killer cells". European Journal of Immunology. 33 (5): 1235–41. S2CID 10724743.
- Marcenaro E, Augugliaro R, Falco M, Castriconi R, Parolini S, Sivori S, et al. (December 2003). "CD59 is physically and functionally associated with natural cytotoxicity receptors and activates human NK cell-mediated cytotoxicity". European Journal of Immunology. 33 (12): 3367–76. S2CID 40345630.
- Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, et al. (December 2003). "Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse". Genome Research. 13 (12): 2621–36. PMID 14656967.
- Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, et al. (May 2005). "Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias". Blood. 105 (9): 3615–22. PMID 15657183.
- Poggi A, Massaro AM, Negrini S, Contini P, Zocchi MR (March 2005). "Tumor-induced apoptosis of human IL-2-activated NK cells: role of natural cytotoxicity receptors". Journal of Immunology. 174 (5): 2653–60. PMID 15728472.
- Vitale M, Della Chiesa M, Carlomagno S, Pende D, Aricò M, Moretta L, Moretta A (July 2005). "NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor". Blood. 106 (2): 566–71. PMID 15784725.
- Warren HS, Jones AL, Freeman C, Bettadapura J, Parish CR (July 2005). "Evidence that the cellular ligand for the human NK cell activation receptor NKp30 is not a heparan sulfate glycosaminoglycan". Journal of Immunology. 175 (1): 207–12. PMID 15972650.
- Joyce MG, Tran P, Zhuravleva MA, Jaw J, Colonna M, Sun PD (April 2011). "Crystal structure of human natural cytotoxicity receptor NKp30 and identification of its ligand binding site". Proceedings of the National Academy of Sciences of the United States of America. 108 (15): 6223–8. PMID 21444796.
External links
- NCR3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Natural cytotoxicity triggering receptor 3 (NCR3)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.