NKG2D的结构与功能
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摘要
目的:探讨NK细胞活化性受体NKG2D的结构与功能。方法:采用回顾性分析法系统归纳总结国内外近20年有关NKG2D结构与功能的研究资料。结果:NKG2D是表达于NK细胞表面的Ⅱ型膜蛋白受体,其基因定位于12p12. 3-p13. 1,含10个外显子和9个内含子。NKG2D单聚体蛋白质的三维结构含2个α螺旋,2个β片层,4个二硫键,主要依靠接头蛋白传递活化信号。NKG2D以同源二聚体形式结合DAP10,并使之磷酸化,然后与肿瘤表面的相应配体MICA、MICB、ULBPs结合,激活PI3K、PLCγ2、JNK-cJunN等信号通路,使NK细胞TNF-α、IFN-γ、颗粒酶释放分泌增加,Fas L、TRAIL表达上调,对肿瘤细胞发挥细胞毒性效应。结论:活化的NK细胞高表达NKG2D,而肿瘤细胞则高表达MICA、MICB、ULBPs,活化NK细胞表面的NKG2D与MICA、MICB、ULBPs结合,触发NK细胞释放多种细胞因子、分泌颗粒酶、表达Fas L、TRAIL,使靶细胞溶解,多途径发挥抗肿瘤作用。
Objective: To summarize the structure and function of NK cell activated receptor( NKG2 D). Methods: The data of NKG2 D and its function in activating NK cells in recent twenty years at home and abroad were systematically summarized by retrospective analysis. Results: NKG2 D was a type Ⅱ membrane protein receptor expressed on the surface of NK cells,which gene was located in 12 p12. 3-p13. 1,and consisted of 10 exons and 9 introns. The three-dimensional structure of NKG2 D monomeric protein contained two α-helices,two β-lamellae and four disulfide bonds,and mainly activates signal transduction by adaptor protein( DAP).NKG2 D was bound to DAP10 in homologous two dimer form and then could be phosphorylated. After NKG2 D on the surface of activated NK cells combine with the corresponding ligands( such as MICA,MICB,and ULBPs) on the surface of tumor cells,the signaling pathways of PI3 K,PLC gamma 2,JNK-cJunN and others should be activated,and the release and secretion of TNF-alpha,IFN-gamma,and granzyme from NK cells should be increased,and the expression of Fas L and TRAIL was up-regulated,which had multiple cytotoxic effects on hepatocellular carcinoma cells. Conclusion: Activated NK cells can express high level of NKG2 D. However,MICA,MICB and ULBPs all can be expressed on surface of tumor cells. NKG2 D on the surface of activated NK cells can combine with MICA,MICB and ULBPs,and triggers NK cells to release a variety of cytokines,secrete granzyme,express Fas L and TRAIL. It plays an important role in anti-tumor effects through multiple ways.
Objective: To summarize the structure and function of NK cell activated receptor( NKG2 D). Methods: The data of NKG2 D and its function in activating NK cells in recent twenty years at home and abroad were systematically summarized by retrospective analysis. Results: NKG2 D was a type Ⅱ membrane protein receptor expressed on the surface of NK cells,which gene was located in 12 p12. 3-p13. 1,and consisted of 10 exons and 9 introns. The three-dimensional structure of NKG2 D monomeric protein contained two α-helices,two β-lamellae and four disulfide bonds,and mainly activates signal transduction by adaptor protein( DAP).NKG2 D was bound to DAP10 in homologous two dimer form and then could be phosphorylated. After NKG2 D on the surface of activated NK cells combine with the corresponding ligands( such as MICA,MICB,and ULBPs) on the surface of tumor cells,the signaling pathways of PI3 K,PLC gamma 2,JNK-cJunN and others should be activated,and the release and secretion of TNF-alpha,IFN-gamma,and granzyme from NK cells should be increased,and the expression of Fas L and TRAIL was up-regulated,which had multiple cytotoxic effects on hepatocellular carcinoma cells. Conclusion: Activated NK cells can express high level of NKG2 D. However,MICA,MICB and ULBPs all can be expressed on surface of tumor cells. NKG2 D on the surface of activated NK cells can combine with MICA,MICB and ULBPs,and triggers NK cells to release a variety of cytokines,secrete granzyme,express Fas L and TRAIL. It plays an important role in anti-tumor effects through multiple ways.
引文
[1]Molfetta R,Quatrini L,Zitti B,et al.Regulation of NKG2DExpression and Signaling by Endocytosis[J].Trends Immunol,2016,37(11):790-802.
[2]López-Cobo S,Romera-Cárdenas G,García-Cuesta EM,et al.Transfer of the human NKG2D ligands UL16 binding proteins(ULBP)1-3 is related to lytic granule release and leads to ligand retransfer and killing of ULBP-recipient natural killer cells[J].Immunology,2015,146(1):70-80.
[3]Houchins JP,Yabe T,Mc Sherry C,et al.DNA sequence analysis of NKG2,a family of related c DNA clones encoding type II integral membrane proteins on human natural killer cells[J].J Exp Med,1991,173(4):1017-1020.
[4]Lee DH,Nam JY,Chang Y,et al.Synergistic effect of cytokineinduced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model[J].Cancer Biol Ther,2017,18(1):67-75.
[5]Waggoner SN,Reighard SD,Gyurova IE,et al.Roles of natural killer cells in antiviral immunity[J].Curr Opin Virol,2016,16:15-23.
[6]Popko K,Górska E.The role of natural killer cells in pathogenesis of autoimmune diseases[J].Cent Eur J Immunol,2015,40(4):470-476.
[7]Tang L,Bai J,Chung CS,et al.Programmed cell death receptor ligand 1 modulates the regulatory T cells'capacity to repress shock/sepsis-induced indirect acute lung injury by recruiting phosphatase SRC homology region2 domain-containing phosphatase1[J].Shock,2015,43(1):47-54.
[8]Wen LZ,Ding K,Wang ZR,et al.SHP-1 acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression[J].Cancer Res,2018,78(16):4680-4691.
[9]Ho EL,Heusel JW,Brown MG,et al.Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells[J].Proc Natl Acad Sci USA,1998,95(11):6320-6325.
[10]Dissen E,Ryan JC,Seaman WE,et al.An autosomal dominant locus,Nka,mapping to the Ly-49 region of a rat natural killer(NK)gene complex,controls NK cell lysis of allogeneic lymphocytes[J].J Exp Med,1996,183(5):2197-2207.
[11]Ritter C,Fan K,Paulson KG,et al.Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma[J].Sci Rep,2016,6:21678.
[12]Imai K,Hayashi T,Yamaoka M,et al.Effects of NKG2Dhaplotypes on the cell-surface expression of NKG2D protein on natural killer and CD8 T cells of peripheral blood among atomicbomb survivors[J].Hum Immunol,2012,73(6):686-691.
[13]王惠明.免疫受体NKG2D介导的细胞免疫及其与疾病的关系[J].国际免疫学杂志,2008,31(6):415-419.Wang HM.NKG2D-mediated cellular immune response and its role in disease[J].Int J Immunol,2008,31(6):415-419.
[14]Glienke J,Sobanov Y,Brostjan C,et al.The genomic organization of NKG2C,E,F,and D receptor genes in the human natural killer gene complex[J].Immunogenetics,1998,48(3):163-173.
[15]Berg SF,Dissen E,Westgaard IH,et al.Molecular characterization of rat NKR-P2,a lectin-like receptor expressed by NK cells and resting T cells[J].Int Immunol,1998,10(4):379-385.
[16]Shum BP,Flodin LR,Muir DG,et al.Conservation and variation in human and common chimpanzee CD94 and NKG2 genes[J].JImmunol,2002,168(1):240-252.
[17]Houchins JP,Yabe T,Mc Sherry C,et al.DNA sequence analysis of NKG2,a family of related c DNA clones encoding type IIintegral membrane proteins on human natural killer cells[J].JExp Med,1991,173(4):1017-1020.
[18]Diefenbach A,Tomasello E,Lucas M,et al.Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D[J].Nat Immunol,2002,3(12):1142-1149.
[19]Guerra N,Tan YX,Joncker NT,et al.NKG2D-deficient mice are defect in tumor surveillance in models of spontaneous malignancy[J].Immunity,2008,28(4):571-580.
[20]Li P,Morris DL,Willcox BE,et al.Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA[J].Nat Immunol,2001,2(5):443-451.
[21]Raulet DH,Gasser S,Gowen BG,et al.Regulation of ligands for the NKG2D activating receptor[J].Annu Rev Immunol,2013,31:413-441.
[22]Karimi MA,Aguilar O,Zou B,et al.A truncated human NKG2Dsplice isoform negatively regulates NKG2D-mediated function[J].J Immunol,2014,193(6):2764-2771.
[23]Segovis CM,Schoon RA,Dick CJ,et al.s PI3K links NKG2Dsignaling to a CrkL pathway involved in natural killer cell adhesion,polarity,and granule secretion[J].J Immunol,2009,182(11):6933-6942.
[24]Sagiv A,Burton DG,Moshayev Z,et al.NKG2D ligands mediate immunosurveillance of senescent cells[J].Aging(Albany NY),2016,8(2):328-344.
[25]Wang Y,Wang W,Shen C,et al.NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection[J].Sci Rep,2017,7(1):88.
[26]Huang WC,Easom NJ,Tang XZ,et al.T cells infiltrating diseased liver express ligands for the NKG2D stress surveillance system[J].J Immunol,2017,198(3):1172-1182.
[27]Chen H,Zhidan W,Xia R,et al.Scorpion venom activates natural killer cells in hepatocellular carcinoma via the NKG2D-MICApathway[J].Int Immunopharmacol,2016,35:307-314.
[28]Zhang ZX,Wang S,Huang X,et al.NK cells induce apoptosis in tubular epithelial cells and contribute to renal ischemiareperfusion injury[J].J Immunol,2008,181(11):7489-7498.
[29]王健,曹伟娅.外周血和脐血CIK细胞杀伤机制、效果研究进展[J].现代免疫学,2017,37(2):165-169.Wang J,Cao WY.Research progress in the cytotoxicity of CIKcells from peripheral blood and cord blood[J].Curr Immunol,2017,37(2):165-169.
[30]王健,刘晓蕊.CIK细胞抗肿瘤研究进展[J].现代免疫学,2017,37(3):258-262.Wang J,Liu XR.Advances in research of CIK cells against tumor[J].Curr Immunol,2017,37(2):165-169.
[31]王健,韩忠燕,周娜.CXCL8及其受体CXCR1、CXCR2在慢性乙肝患者外周血PMNs中的表达[J].中国免疫学杂志,2015,31(3):375-379,383.Wang J,Han ZY,Zhou N.Expression of CXCL8 and its receptors(CXCR1 and CXCR2)in peripheral blood neutrophils of chronic hepatitis B[J].Chin J Immunol,2015,31(3):375-379,383.
[32]毕惠娟,陈建民,陈静静,等.CXCR1、CXCR2及CXCL8在乙型相关肝癌中的表达及临床意义[J].中国免疫学杂志,2017,33(6):895-899.Bi HJ,Chen JM,Chen JJ,et al.Expressions and clinical significance of CXC chemokine receptor 1 and 2 and CXCL8 in hepatitis B related hepatocellular carcinoma[J].Chin J Immunol,2017,33(6):895-899.
[2]López-Cobo S,Romera-Cárdenas G,García-Cuesta EM,et al.Transfer of the human NKG2D ligands UL16 binding proteins(ULBP)1-3 is related to lytic granule release and leads to ligand retransfer and killing of ULBP-recipient natural killer cells[J].Immunology,2015,146(1):70-80.
[3]Houchins JP,Yabe T,Mc Sherry C,et al.DNA sequence analysis of NKG2,a family of related c DNA clones encoding type II integral membrane proteins on human natural killer cells[J].J Exp Med,1991,173(4):1017-1020.
[4]Lee DH,Nam JY,Chang Y,et al.Synergistic effect of cytokineinduced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model[J].Cancer Biol Ther,2017,18(1):67-75.
[5]Waggoner SN,Reighard SD,Gyurova IE,et al.Roles of natural killer cells in antiviral immunity[J].Curr Opin Virol,2016,16:15-23.
[6]Popko K,Górska E.The role of natural killer cells in pathogenesis of autoimmune diseases[J].Cent Eur J Immunol,2015,40(4):470-476.
[7]Tang L,Bai J,Chung CS,et al.Programmed cell death receptor ligand 1 modulates the regulatory T cells'capacity to repress shock/sepsis-induced indirect acute lung injury by recruiting phosphatase SRC homology region2 domain-containing phosphatase1[J].Shock,2015,43(1):47-54.
[8]Wen LZ,Ding K,Wang ZR,et al.SHP-1 acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression[J].Cancer Res,2018,78(16):4680-4691.
[9]Ho EL,Heusel JW,Brown MG,et al.Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells[J].Proc Natl Acad Sci USA,1998,95(11):6320-6325.
[10]Dissen E,Ryan JC,Seaman WE,et al.An autosomal dominant locus,Nka,mapping to the Ly-49 region of a rat natural killer(NK)gene complex,controls NK cell lysis of allogeneic lymphocytes[J].J Exp Med,1996,183(5):2197-2207.
[11]Ritter C,Fan K,Paulson KG,et al.Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma[J].Sci Rep,2016,6:21678.
[12]Imai K,Hayashi T,Yamaoka M,et al.Effects of NKG2Dhaplotypes on the cell-surface expression of NKG2D protein on natural killer and CD8 T cells of peripheral blood among atomicbomb survivors[J].Hum Immunol,2012,73(6):686-691.
[13]王惠明.免疫受体NKG2D介导的细胞免疫及其与疾病的关系[J].国际免疫学杂志,2008,31(6):415-419.Wang HM.NKG2D-mediated cellular immune response and its role in disease[J].Int J Immunol,2008,31(6):415-419.
[14]Glienke J,Sobanov Y,Brostjan C,et al.The genomic organization of NKG2C,E,F,and D receptor genes in the human natural killer gene complex[J].Immunogenetics,1998,48(3):163-173.
[15]Berg SF,Dissen E,Westgaard IH,et al.Molecular characterization of rat NKR-P2,a lectin-like receptor expressed by NK cells and resting T cells[J].Int Immunol,1998,10(4):379-385.
[16]Shum BP,Flodin LR,Muir DG,et al.Conservation and variation in human and common chimpanzee CD94 and NKG2 genes[J].JImmunol,2002,168(1):240-252.
[17]Houchins JP,Yabe T,Mc Sherry C,et al.DNA sequence analysis of NKG2,a family of related c DNA clones encoding type IIintegral membrane proteins on human natural killer cells[J].JExp Med,1991,173(4):1017-1020.
[18]Diefenbach A,Tomasello E,Lucas M,et al.Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D[J].Nat Immunol,2002,3(12):1142-1149.
[19]Guerra N,Tan YX,Joncker NT,et al.NKG2D-deficient mice are defect in tumor surveillance in models of spontaneous malignancy[J].Immunity,2008,28(4):571-580.
[20]Li P,Morris DL,Willcox BE,et al.Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA[J].Nat Immunol,2001,2(5):443-451.
[21]Raulet DH,Gasser S,Gowen BG,et al.Regulation of ligands for the NKG2D activating receptor[J].Annu Rev Immunol,2013,31:413-441.
[22]Karimi MA,Aguilar O,Zou B,et al.A truncated human NKG2Dsplice isoform negatively regulates NKG2D-mediated function[J].J Immunol,2014,193(6):2764-2771.
[23]Segovis CM,Schoon RA,Dick CJ,et al.s PI3K links NKG2Dsignaling to a CrkL pathway involved in natural killer cell adhesion,polarity,and granule secretion[J].J Immunol,2009,182(11):6933-6942.
[24]Sagiv A,Burton DG,Moshayev Z,et al.NKG2D ligands mediate immunosurveillance of senescent cells[J].Aging(Albany NY),2016,8(2):328-344.
[25]Wang Y,Wang W,Shen C,et al.NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection[J].Sci Rep,2017,7(1):88.
[26]Huang WC,Easom NJ,Tang XZ,et al.T cells infiltrating diseased liver express ligands for the NKG2D stress surveillance system[J].J Immunol,2017,198(3):1172-1182.
[27]Chen H,Zhidan W,Xia R,et al.Scorpion venom activates natural killer cells in hepatocellular carcinoma via the NKG2D-MICApathway[J].Int Immunopharmacol,2016,35:307-314.
[28]Zhang ZX,Wang S,Huang X,et al.NK cells induce apoptosis in tubular epithelial cells and contribute to renal ischemiareperfusion injury[J].J Immunol,2008,181(11):7489-7498.
[29]王健,曹伟娅.外周血和脐血CIK细胞杀伤机制、效果研究进展[J].现代免疫学,2017,37(2):165-169.Wang J,Cao WY.Research progress in the cytotoxicity of CIKcells from peripheral blood and cord blood[J].Curr Immunol,2017,37(2):165-169.
[30]王健,刘晓蕊.CIK细胞抗肿瘤研究进展[J].现代免疫学,2017,37(3):258-262.Wang J,Liu XR.Advances in research of CIK cells against tumor[J].Curr Immunol,2017,37(2):165-169.
[31]王健,韩忠燕,周娜.CXCL8及其受体CXCR1、CXCR2在慢性乙肝患者外周血PMNs中的表达[J].中国免疫学杂志,2015,31(3):375-379,383.Wang J,Han ZY,Zhou N.Expression of CXCL8 and its receptors(CXCR1 and CXCR2)in peripheral blood neutrophils of chronic hepatitis B[J].Chin J Immunol,2015,31(3):375-379,383.
[32]毕惠娟,陈建民,陈静静,等.CXCR1、CXCR2及CXCL8在乙型相关肝癌中的表达及临床意义[J].中国免疫学杂志,2017,33(6):895-899.Bi HJ,Chen JM,Chen JJ,et al.Expressions and clinical significance of CXC chemokine receptor 1 and 2 and CXCL8 in hepatitis B related hepatocellular carcinoma[J].Chin J Immunol,2017,33(6):895-899.
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