小鼠甘露糖受体中CR结构域的表达、纯化及其功能的初步研究
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摘要
甘露糖受体(MR)为甘露糖受体家族中的一员,属于C-型凝集素受体。甘露糖受体广泛分布于体内的各种组织,主要表达于髓样细胞系,包括非成熟的树突状细胞和巨噬细胞亚群。此外,肝的窦状隙细胞,人的表皮朗罕氏细胞,肾小球系膜细胞,内皮细胞亚群,气管平滑肌细胞,视网膜上皮细胞等都发现了甘露糖受体的表达。甘露糖受体在调节内环境的稳定,介导先天性免疫及获得性免疫应答中都有其明确的作用。此外,甘露糖受体可能参与了肿瘤的淋巴道转移以及肿瘤微环境中肿瘤的免疫逃避。
甘露糖受体为相对分子量为175kDa的一种I型跨膜受体,由五部分组成:N-末端富含半胱氨酸结构域(CR);II型纤连蛋白重复序列(FNII);8个C-型凝集素样结构域(CTLDs);跨膜结构域;C末端的胞质结构域.。甘露糖受体能够通过不同的结构域与内源性以及外源性配体结合。
富含半胱氨酸结构域(CR)为甘露糖受体的N端序列,专门识别内源性的酸性聚糖,能够与糖蛋白末端的4-硫酸化,3-硫酸化的N-乙酰基葡萄糖胺以及3-硫酸化的半乳糖结合。体内的多种激素,例如,垂体激素,促黄体生成素,促甲状腺激素都表达该硫酸化的结构。此外,在淋巴结组织中发现了富含半胱氨酸结构域的多种配体,包括唾液酸黏附素(Sn),CD45以及一些有待于进一步鉴定的潜在配体。
L-选择素在正常情况下为淋巴细胞的归巢受体.淋巴细胞表面的黏附分子与淋巴管内皮细胞通过多环节的相互作用介导了淋巴细胞的归巢过程。其中淋巴细胞表达的L-选择素在此过程中发挥了重要的作用,L-选择素通过与HEVs表面表达的外周淋巴结黏附素(PNAds)相互作用而进入淋巴系统。近来研究发现,人的输出淋巴管内皮有MR的表达,而且淋巴细胞可能通过表达的L-选择素与输出淋巴管内皮表达
Mannose receptor is one of the mannose receptor family and belongs to C-type lectin receptor.Mannose receptor distributes extensively in vivo ,which is predominantly expressed on immune cells of myeloid lineage, especially subsets of dendriric cells (DC) and tissue macrophages .In addition,it is now clear that it is also expressed in hepatic sinusoidal cells, human epidermal Langerhans cells, kidney mesangial cells, subsets of endothelial cells, smooth muscles cells from the trachea and retinal pigment epithelium. A number of functions have been ascribed to mannose receptor including modulating tissue homeostasis, regulating innate immunity and adaptive immunity.In addition, mannose receptor maybe take part in tumor lymphatic pathway metastasis and tumor immune evasion in tummor microenvironment.
Mannose receptor is a 175 kDa I type transmembrane receptor consisting of five domains: a cysteine rich amino terminus; a fibronectin type II repeat region; 8 calcium dependent carbohydrate recognition domains (CRDs; CRD1-8); a transmembrane domain and a cytoplasmic domain. Mannose receptor can bind endogenetic and extrinsic ligand through different domains.
Cysteine rich domain is the N-terminal sequence of mannose receptor and specifically binds acidic glycans terminating in either N-acetyl- galactosamine sulphated at position 3 or 4, or 3-sulphated galactose such as those found on the pituitary hormones,lutropin (luteinizing hormone) and thyrotropin.Furthermore, it has been found a number of ligands of CR domain in lymph node such as sialoadhesin,CD45 and many ligands
甘露糖受体为相对分子量为175kDa的一种I型跨膜受体,由五部分组成:N-末端富含半胱氨酸结构域(CR);II型纤连蛋白重复序列(FNII);8个C-型凝集素样结构域(CTLDs);跨膜结构域;C末端的胞质结构域.。甘露糖受体能够通过不同的结构域与内源性以及外源性配体结合。
富含半胱氨酸结构域(CR)为甘露糖受体的N端序列,专门识别内源性的酸性聚糖,能够与糖蛋白末端的4-硫酸化,3-硫酸化的N-乙酰基葡萄糖胺以及3-硫酸化的半乳糖结合。体内的多种激素,例如,垂体激素,促黄体生成素,促甲状腺激素都表达该硫酸化的结构。此外,在淋巴结组织中发现了富含半胱氨酸结构域的多种配体,包括唾液酸黏附素(Sn),CD45以及一些有待于进一步鉴定的潜在配体。
L-选择素在正常情况下为淋巴细胞的归巢受体.淋巴细胞表面的黏附分子与淋巴管内皮细胞通过多环节的相互作用介导了淋巴细胞的归巢过程。其中淋巴细胞表达的L-选择素在此过程中发挥了重要的作用,L-选择素通过与HEVs表面表达的外周淋巴结黏附素(PNAds)相互作用而进入淋巴系统。近来研究发现,人的输出淋巴管内皮有MR的表达,而且淋巴细胞可能通过表达的L-选择素与输出淋巴管内皮表达
Mannose receptor is one of the mannose receptor family and belongs to C-type lectin receptor.Mannose receptor distributes extensively in vivo ,which is predominantly expressed on immune cells of myeloid lineage, especially subsets of dendriric cells (DC) and tissue macrophages .In addition,it is now clear that it is also expressed in hepatic sinusoidal cells, human epidermal Langerhans cells, kidney mesangial cells, subsets of endothelial cells, smooth muscles cells from the trachea and retinal pigment epithelium. A number of functions have been ascribed to mannose receptor including modulating tissue homeostasis, regulating innate immunity and adaptive immunity.In addition, mannose receptor maybe take part in tumor lymphatic pathway metastasis and tumor immune evasion in tummor microenvironment.
Mannose receptor is a 175 kDa I type transmembrane receptor consisting of five domains: a cysteine rich amino terminus; a fibronectin type II repeat region; 8 calcium dependent carbohydrate recognition domains (CRDs; CRD1-8); a transmembrane domain and a cytoplasmic domain. Mannose receptor can bind endogenetic and extrinsic ligand through different domains.
Cysteine rich domain is the N-terminal sequence of mannose receptor and specifically binds acidic glycans terminating in either N-acetyl- galactosamine sulphated at position 3 or 4, or 3-sulphated galactose such as those found on the pituitary hormones,lutropin (luteinizing hormone) and thyrotropin.Furthermore, it has been found a number of ligands of CR domain in lymph node such as sialoadhesin,CD45 and many ligands
引文
1. Irjala, H., Johansson, E. L., Grenman, R., Alanen, K., Salmi, M., and Jalkanen, S.Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte bindingto lymphatic endothelium. J. Exp. Med., 194: 1033–1042, 2001.
2. Mannose Receptor (MR) and Common Lymphatic Endothelial and Vascular Endothelial Receptor (CLEVER)-1 Direct the Binding of Cancer Cells to the Lymph Vessel Endothelium1 Heikki Irjala, Kalle Alanen, Reidar Gre′nman, Pa¨ivi Heikkila¨, Heikki Joensuu, and Sirpa Jalkanen2
3. 刘敏、王莉芬、朱杰等。L-选择蛋白可能介导小鼠肝癌细胞经淋巴道转移的研究。解剖学报,2004,35(5):502-506。
4. 刘敏、朱杰、杨佩满等。L-选择蛋白在小鼠肝癌细胞 Hca-F 和 Hca-P 的表达及与肿瘤转移潜能的相关性。解剖科学进展,2003,9(2):100-104。
5. 吴乃虎。基因工程原理 第二版[上册]。科学出版社,1998。
6. David L.Spector,Robert D.Goldman,Leslie A.Leinwand.Cell:A Laboratory Manual.Cold Spring Harbor Laboratory Press,1998.
7. 卢圣栋。现代分子生物学实验技术(第二版)1999。
8. 温伟红,杨安钢。抗人单链抗体基因的构建及其在 COS-7 细胞中的表达。Journal of Experiment Hematology 2000;8(1)
1. D. Fiete, J.U. Baenziger, Isolation of the SO4– 4-GalNAcbeta1, 4GlcNAcbeta1, 2Manalpha-specific receptor from rat liver, J. Biol.Chem. 272 (1997) 14629– 14637.
2. D.J. Fiete, M.C. Beranek, J.U. Baenziger, A CR domain ofthe ‘‘mannose’’ receptor mediates GalNAc-4-SO
3. C. Leteux, W. Chai, R.W. Loveless, C.T. Yuen, L. Uhlin-Hansen, Y.Combarnous, M. Jankovic, S.C. Maric, Z. Misulovin, M.C. Nussenzweig,F. Ten, The CR domain of the macrophage mannosereceptor is a multispecific lectin that recognizes chondroitin sulfatesA and B and sulfated oligosaccharides of blood group Lewis(a) andLewis(x) types in addition to the sulfated N-glycans of lutropin, J.Exp. Med. 91 (2000) 1117–1126.
4. L. Martinez-Pomares, S. Gordon, Potential role of the mannose receptorin antigen transport, Immunol. Lett. 65 (1999) 9 – 13.
5. Pomares LM, Linehan SA , Taylor PR , et al . Binding properties of themannose receptor [J ] . Immunobiology , 2001 , 204(5) : 5272535.
6. M.E. Taylor, K. Bezouska, K. Drickamer, Contribution to ligandbinding by multiple carbohydrate-recognition domains in the macrophagemannose receptor, J. Biol. Chem. 267 (1992) 1719–1726.
7. A. Schweizer, P.D. Stahl, J. Rohrer, A di-aromatic motif in the cytosolictail of the mannose receptor mediates endosomal sorting, J.Biol. Chem. 275 (2000) 29694– 29700.
8. J. Lu, C. Teh, U. Kishore, K.B.M. Reid, Collectins and ficolins:sugar pattern recognition molecules of the mammalian innate immune system, Biochim. Biophys. Acta 1572 (2002) 387–400.
9. R.A. Ezekowitz, K. Sastry, P. Bailly, A.Warner, Molecular characterizationof the human macrophage mannose receptor: demonstrationof multiple carbohydrate recognition-like domains and phagocytosisof yeasts in Cos-1 cells, J. Exp. Med. 172 (1990) 1785– 1794.
10. R.A. Ezekowitz, D.J. Williams, H. Koziel, M.Y. Armstrong, A.Warner, F.F. Richards, R.M. Rose, Uptake of Pneumocystis cariniimediated by the macrophage mannose receptor, Nature 351 (1991)155– 158.
11. Absence of the Macrophage Mannose Receptor in Mice Does NotIncreaseSusceptibility to Pneumocystis carinii Infection In VivoSteve D. Swain, Sena J. Lee,Michel C. Nussenzweig,2 and Allen G.
12. L.S. Schlesinger, Macrophage phagocytosis of virulent but not attenuatedstrains of Mycobacterium tuberculosis is mediated by mannosereceptors in addition to complement receptors, J. Immunol. 150(1993) 2920– 2930.
13. I. Mellman, Endocytosis and molecular sorting, Annu. Rev. CellDev. Biol. 12 (1996) 575–625.
14. F. Sallusto, M. Cella, C. Danieli, A. Lanzavecchia, Dendritic cellsuse macropinocytosis and the mannose receptor toconcentrate macromoleculesin the major histocompatibility complex class II compartment:downregulation by cytokines and bacterial products, J.Exp. Med. 182 (1995) 389– 400.
15. T.I. Prigozy, P.A. Sieling, D. Clemens, P.L. Stewart, S.M. Behar, S.A.Porcelli, M.B. Brenner, R.L. Modlin, M. Kronenberg, The mannosereceptor delivers lipoglycan antigens to endosomes for presentation toT cells by CD1b molecules, Immunity 6(1997) 187–197.
16. S.A. Linehan, L. Martinez-Pomares, P.D. Stahl, S. Gordon, Mannosereceptor and its putative ligands in normal murine lymphoid andnonlymphoid organs: In situ expression of mannose receptor byselected macrophages, endothelial cells, perivascular microglia, andmesangial cells, but not dendritic cells, J. Exp. Med. 189 (1999)1961– 1972.
17. L. Martinez-Pomares, M. Kosco-Vilbois, E. Darley, P. Tree, S. Herren,J.Y. Bonnefoy, S. Gordon, Fc chimeric protein containing the cysteinerichdomain of the murine mannose receptor binds to macrophagesfrom splenic marginal zone and lymph node subcapsular sinus and togerminal centers, J. Exp. Med. 184 (1996) 1927– 1937.
18. S.A. Linehan, L. Martinez-Pomares, R.P. da Silva, S. Gordon, Endogenousligands of carbohydrate recognition domains of the mannosereceptor in murine macrophages, endothelial cells and secretorycells; potential relevance to inflammation and immunity, Eur. J. Immunol.31 (2001) 1857– 1866.
19. Sica A, Saccani A, Bottazzi B, Polentamtti N, VecchiA, van Damme J, Mantovani A. Autocrine production of IL-10 mediates defective IL-12 production andNF- kappa B activation in tumor-associated macrophages.J Immunol 2000;164{2):762.
20. Hiltbold EM, Alter MD, Ciborowski P, Finn OJ.Presentation of MUCl tiimor antigen by class I MHC and CTL flinction correlate with the giycosylationstate otthe protein taken up by dendritic cells. Cell Immunol 1999;194(2):143.
21. Monti P, Leone EB, Zerbi A, Balzano G, Cainarca S,Sordi D, PontoiUo M, Mercalli A, Di Carlo avena P, Piemonti L. Tumor-derived MUCl mucins interactwith ditferentiating monocytes and induce IL-10high/lL-12 low "regulator)'" dendritic cells. J Immunol2004;172(12):7341
22. Irjala, H., Johansson, E. L., Grenman, R., Alanen, K., Salmi, M., and Jalkanen, S.Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte bindingto lymphatic endothelium. J. Exp. Med., 194: 1033–1042, 2001.
2. Mannose Receptor (MR) and Common Lymphatic Endothelial and Vascular Endothelial Receptor (CLEVER)-1 Direct the Binding of Cancer Cells to the Lymph Vessel Endothelium1 Heikki Irjala, Kalle Alanen, Reidar Gre′nman, Pa¨ivi Heikkila¨, Heikki Joensuu, and Sirpa Jalkanen2
3. 刘敏、王莉芬、朱杰等。L-选择蛋白可能介导小鼠肝癌细胞经淋巴道转移的研究。解剖学报,2004,35(5):502-506。
4. 刘敏、朱杰、杨佩满等。L-选择蛋白在小鼠肝癌细胞 Hca-F 和 Hca-P 的表达及与肿瘤转移潜能的相关性。解剖科学进展,2003,9(2):100-104。
5. 吴乃虎。基因工程原理 第二版[上册]。科学出版社,1998。
6. David L.Spector,Robert D.Goldman,Leslie A.Leinwand.Cell:A Laboratory Manual.Cold Spring Harbor Laboratory Press,1998.
7. 卢圣栋。现代分子生物学实验技术(第二版)1999。
8. 温伟红,杨安钢。抗人单链抗体基因的构建及其在 COS-7 细胞中的表达。Journal of Experiment Hematology 2000;8(1)
1. D. Fiete, J.U. Baenziger, Isolation of the SO4– 4-GalNAcbeta1, 4GlcNAcbeta1, 2Manalpha-specific receptor from rat liver, J. Biol.Chem. 272 (1997) 14629– 14637.
2. D.J. Fiete, M.C. Beranek, J.U. Baenziger, A CR domain ofthe ‘‘mannose’’ receptor mediates GalNAc-4-SO
3. C. Leteux, W. Chai, R.W. Loveless, C.T. Yuen, L. Uhlin-Hansen, Y.Combarnous, M. Jankovic, S.C. Maric, Z. Misulovin, M.C. Nussenzweig,F. Ten, The CR domain of the macrophage mannosereceptor is a multispecific lectin that recognizes chondroitin sulfatesA and B and sulfated oligosaccharides of blood group Lewis(a) andLewis(x) types in addition to the sulfated N-glycans of lutropin, J.Exp. Med. 91 (2000) 1117–1126.
4. L. Martinez-Pomares, S. Gordon, Potential role of the mannose receptorin antigen transport, Immunol. Lett. 65 (1999) 9 – 13.
5. Pomares LM, Linehan SA , Taylor PR , et al . Binding properties of themannose receptor [J ] . Immunobiology , 2001 , 204(5) : 5272535.
6. M.E. Taylor, K. Bezouska, K. Drickamer, Contribution to ligandbinding by multiple carbohydrate-recognition domains in the macrophagemannose receptor, J. Biol. Chem. 267 (1992) 1719–1726.
7. A. Schweizer, P.D. Stahl, J. Rohrer, A di-aromatic motif in the cytosolictail of the mannose receptor mediates endosomal sorting, J.Biol. Chem. 275 (2000) 29694– 29700.
8. J. Lu, C. Teh, U. Kishore, K.B.M. Reid, Collectins and ficolins:sugar pattern recognition molecules of the mammalian innate immune system, Biochim. Biophys. Acta 1572 (2002) 387–400.
9. R.A. Ezekowitz, K. Sastry, P. Bailly, A.Warner, Molecular characterizationof the human macrophage mannose receptor: demonstrationof multiple carbohydrate recognition-like domains and phagocytosisof yeasts in Cos-1 cells, J. Exp. Med. 172 (1990) 1785– 1794.
10. R.A. Ezekowitz, D.J. Williams, H. Koziel, M.Y. Armstrong, A.Warner, F.F. Richards, R.M. Rose, Uptake of Pneumocystis cariniimediated by the macrophage mannose receptor, Nature 351 (1991)155– 158.
11. Absence of the Macrophage Mannose Receptor in Mice Does NotIncreaseSusceptibility to Pneumocystis carinii Infection In VivoSteve D. Swain, Sena J. Lee,Michel C. Nussenzweig,2 and Allen G.
12. L.S. Schlesinger, Macrophage phagocytosis of virulent but not attenuatedstrains of Mycobacterium tuberculosis is mediated by mannosereceptors in addition to complement receptors, J. Immunol. 150(1993) 2920– 2930.
13. I. Mellman, Endocytosis and molecular sorting, Annu. Rev. CellDev. Biol. 12 (1996) 575–625.
14. F. Sallusto, M. Cella, C. Danieli, A. Lanzavecchia, Dendritic cellsuse macropinocytosis and the mannose receptor toconcentrate macromoleculesin the major histocompatibility complex class II compartment:downregulation by cytokines and bacterial products, J.Exp. Med. 182 (1995) 389– 400.
15. T.I. Prigozy, P.A. Sieling, D. Clemens, P.L. Stewart, S.M. Behar, S.A.Porcelli, M.B. Brenner, R.L. Modlin, M. Kronenberg, The mannosereceptor delivers lipoglycan antigens to endosomes for presentation toT cells by CD1b molecules, Immunity 6(1997) 187–197.
16. S.A. Linehan, L. Martinez-Pomares, P.D. Stahl, S. Gordon, Mannosereceptor and its putative ligands in normal murine lymphoid andnonlymphoid organs: In situ expression of mannose receptor byselected macrophages, endothelial cells, perivascular microglia, andmesangial cells, but not dendritic cells, J. Exp. Med. 189 (1999)1961– 1972.
17. L. Martinez-Pomares, M. Kosco-Vilbois, E. Darley, P. Tree, S. Herren,J.Y. Bonnefoy, S. Gordon, Fc chimeric protein containing the cysteinerichdomain of the murine mannose receptor binds to macrophagesfrom splenic marginal zone and lymph node subcapsular sinus and togerminal centers, J. Exp. Med. 184 (1996) 1927– 1937.
18. S.A. Linehan, L. Martinez-Pomares, R.P. da Silva, S. Gordon, Endogenousligands of carbohydrate recognition domains of the mannosereceptor in murine macrophages, endothelial cells and secretorycells; potential relevance to inflammation and immunity, Eur. J. Immunol.31 (2001) 1857– 1866.
19. Sica A, Saccani A, Bottazzi B, Polentamtti N, VecchiA, van Damme J, Mantovani A. Autocrine production of IL-10 mediates defective IL-12 production andNF- kappa B activation in tumor-associated macrophages.J Immunol 2000;164{2):762.
20. Hiltbold EM, Alter MD, Ciborowski P, Finn OJ.Presentation of MUCl tiimor antigen by class I MHC and CTL flinction correlate with the giycosylationstate otthe protein taken up by dendritic cells. Cell Immunol 1999;194(2):143.
21. Monti P, Leone EB, Zerbi A, Balzano G, Cainarca S,Sordi D, PontoiUo M, Mercalli A, Di Carlo avena P, Piemonti L. Tumor-derived MUCl mucins interactwith ditferentiating monocytes and induce IL-10high/lL-12 low "regulator)'" dendritic cells. J Immunol2004;172(12):7341
22. Irjala, H., Johansson, E. L., Grenman, R., Alanen, K., Salmi, M., and Jalkanen, S.Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte bindingto lymphatic endothelium. J. Exp. Med., 194: 1033–1042, 2001.