B细胞连接蛋白的结构、功能及其在B细胞相关疾病发展中的作用
|
摘要
B细胞连接蛋白,是B细胞受体通路的关键接头蛋白。B细胞连接蛋白通过自身的结构特性及蛋白互作网络参与调控PLC-γ的活性和Ras通路激活,在B细胞受体信号转导中发挥重要作用,广泛参与调控B细胞的增殖、分化、凋亡及信号传导等过程,并与过敏性疾病、多发性硬化症、染色体组非整倍体、无丙种球蛋白血症、B淋巴细胞白血病、淋巴瘤的发生发展密切相关。本文对B细胞连接蛋白的结构、生物学功能及其在B细胞相关疾病中的作用进行综述:B细胞连接蛋白可与多个效应蛋白协作,激活B细胞受体信号通路,从而影响着B细胞的发育成熟及功能调节;B细胞连接蛋白发生功能性突变,会破坏B细胞稳态并影响B细胞发育成熟,从而导致B细胞相关疾病的发生。全面总结B细胞连接蛋白的生物学功能不仅有助于了解B细胞相关疾病的发生机制,也有望将B细胞连接蛋白作为相关疾病的治疗靶标提供新思路和突破口。
B cell linker(BLNK) is a key linker protein of B cell receptor(BCR) signaling pathway.BLNK participates in the regulation of PLC-γactivity and the activation of Ras pathway through its typical structure and interaction network with other proteins,and is thus widely involved in the regulation of B cell proliferation,differentiation,apoptosis and signal transduction.Furthermore,it is closely related to anaphylactic diseases,multiple sclerosis,chromosomal aneuploidy,aneuglobulinemia,B lymphocytic leukemia and lymphoma.Herein we review the structure and biological function of BLNK and its role in B cell-related diseases.BLNK can cooperate with a series of effective proteins to activate BCR signaling pathway,thereby regulating the development,maturation and function of B cells.The functional mutation of BLNK can destroy the homeostasis of B cells and affect the development and maturation of B cells,which leads to the occurrence of B cell related diseases.A comprehensive understanding of the biological functions of BLNK not only provides insights into the pathogenesis of B cell-related diseases,but also inspires new ideas and helps to find breakthroughs for the treatment of these diseases with BLNK as the therapeutic target.
B cell linker(BLNK) is a key linker protein of B cell receptor(BCR) signaling pathway.BLNK participates in the regulation of PLC-γactivity and the activation of Ras pathway through its typical structure and interaction network with other proteins,and is thus widely involved in the regulation of B cell proliferation,differentiation,apoptosis and signal transduction.Furthermore,it is closely related to anaphylactic diseases,multiple sclerosis,chromosomal aneuploidy,aneuglobulinemia,B lymphocytic leukemia and lymphoma.Herein we review the structure and biological function of BLNK and its role in B cell-related diseases.BLNK can cooperate with a series of effective proteins to activate BCR signaling pathway,thereby regulating the development,maturation and function of B cells.The functional mutation of BLNK can destroy the homeostasis of B cells and affect the development and maturation of B cells,which leads to the occurrence of B cell related diseases.A comprehensive understanding of the biological functions of BLNK not only provides insights into the pathogenesis of B cell-related diseases,but also inspires new ideas and helps to find breakthroughs for the treatment of these diseases with BLNK as the therapeutic target.
引文
[1]Han Y,Xin L,Shi B,et al.Identification and characterisation of the immune response properties of Lampetra japonica BLNK[J].Sci Rep,2016,5(6):25308-16.
[2]Seda V,Mraz M.B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells[J].Eur J Haematol,2015,94(3):193-205.
[3]Kusuyama J,Ai K,Changhwan S,et al.Spleen tyrosine kinase influences the early stages of multilineage differentiation of bone marrow stromal cell lines by regulating phospholipase C gamma activities[J].J Cell Physiol,2018,233(3):118-29.
[4]Szydlowski M,Jablonska E,Juszczynski P.FOXO1 transcription factor:a critical effector of the PI3K-AKT axis in B-Cell development[J].Int Rev Immunol,2014,33(2):146-57.
[5]Bednarski JJ,Pandey R,Schulte E,et al.RAG-mediated DNAdouble-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals[J].J Experim Med,2016,213(2):209-23.
[6]Abdelrasoul H,Werner M,Setz CS,et al.PI3K induces B-cell development and regulates B cell identity[J].Sci Rep,2018,8(1):1327-36.
[7]Polgarova K,Vaskova M,Fronkova E,et al.Quantitative expression of regulatory and differentiation-related genes in the key steps of human hematopoiesis:The LeukoStage Database[J].Differentiation,2016,91(1/3):19-28.
[8]Woyach JA,Ruppert AS,Guinn D,et al.BTKC481S-Mediated resistance to ibrutinib in chronic lymphocytic leukemia[J].J Clin Oncol,2017,35(13):1437-45.
[9]Ndipagbornchi TG,Mauno V.Simulation of the dynamics of primary immunodeficiencies in B cells[J].Front Immunol,2018,(9):1785-93.
[10]Budzyńska PM,Niemel?M,Sarapulov AV,et al.IRF4 deficiency leads to altered BCR signalling revealed by enhanced PI3Kpathway,decreased SHIP expression and defected cytoskeletal responses[J].Scand J Immunol,2015,82(5):418-28.
[11]Mohammad DK,Nore BF,Gustafsson MO,et al.Protein kinase B(AKT)regulates SYK activity and shuttling through 14-3-3 and importin[J].Intern J Biochem Cell Biol,2016,78(1):63-74.
[12]Poe JC,Jia W,Su H,et al.An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD[J].Blood,2017,130(19):2131-45.
[13]Wang J,Sohn H,Sun G,et al.The autoinhibitory C-terminal SH2domain of phospholipase C-γ2 stabilizes B cell receptor signalosome assembly[J].Sci Signal,2014,7(343):a89-95.
[14]Rao A,Luo C,Hogan PG.Transcription factors of the NFAT family:regulation and function[J].Annu Rev Immunol,1997,15(15):707-47.
[15]Patterson HC,Kraus M,Kim Y,et al.The B cell receptor promotes B cell activation and proliferation through a non-ITAM tyrosine in the Ig alpha cytoplasmic domain[J].Immunity,2006,25(1):55-65.
[16]Tsukada S,Baba Y,Dai W.Btk and BLNK in B cell development[J].Adv Immunol,2001,77(5):123-37.
[17]Imamura Y,Oda A,Katahira T,et al.BLNK binds active H-Ras to promote B cell receptor-mediated capping and ERK activation[J].JBiol Chem,2009,284(15):9804-13.
[18]Chuang HC,Wang X,Tan TH.MAP4K family kinases in immunity and inflammation[J].Adv Immunol,2016,129(3):277-314.
[19]Haniuda K,Fukao S,Kodama T,et al.Autonomous membrane IgEsignaling prevents IgE-memory formation[J].Nat Immunol,2016,17(9):1109-17.
[20]Yang ZY,Robinson MJ,Chen XJ,et al.Regulation of B cell fate by chronic activity of the IgE B cell receptor[J].Elife,2016,(5):21238-46.
[21]Hussain RZ,Hayardeny L,Cravens PC,et al.Immune surveillance of the central nervous system in multiple sclerosis-Relevance for therapy and experimental models[J].J Neuroimmunol,2014,276(1/2):9-17.
[22]金桂花,李雪,藤本学,等.B细胞连接蛋白的表达抑制小鼠实验性自身免疫性脑脊髓炎[J].免疫学杂志,2016(10):848-52.
[23]Ray A,Basu S,Williams CB,et al.A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand[J].J Immunol,2012,188(7):3188-98.
[24]Kamino H,Futamura M,Nakamura Y,et al.B-cell linker protein prevents aneuploidy by inhibiting cytokinesis[J].Cancer Sci,2008,99(12):2444-54.
[25]Abu-Arja RF,Chernin LR,Abusin G,et al.Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia[J].Pediatr Blood Cancer,2015,62(9):1674-6.
[26]Lagresle PC,Millili M,Luce S,et al.The BLNK adaptor protein has a nonredundant role in human B-cell differentiation[J].JAllergy Clin Immunol,2014,134(1):145-56.
[27]Nasereddin A,Shamriz O,Keller B,et al.Enteroviral infection in a patient with BLNK adaptor protein deficiency[J].J Clin Immunol,2015,35(4):356-60.
[28]Nasrullayeva GM,Mammadova VR,Khalilova AV,et al.The novel patient with BLNK gene type of agammaglobulinemia[J].Open Access Library J,2017,4(11):1-7.
[29]Hiratsuka T,Takei Y,Ohmori R,et al.ZFP521 contributes to pre-Bcell lymphomagenesis through modulation of the pre-B-cell receptor signaling pathway[J].Oncogene,2016,35(25):3227-38.
[30]Ez-Enr?EC,Rcenas-L?RA,Hidalgo-Miranda A,et al.Gene expression profiling of acute lymphoblastic leukemia in children with?very early relapse[J].Arch Med Res,2016,47(8):644-55.
[31]Katerndahl CD,Heltemes-Harris LM,Willette MJ,et al.Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival[J].Nat Immunol,2017,18(6):694-705.
[32]Imoto N,Hayakawa F,Kurahashi S,et al.B cell linker protein(BLNK)is a selective target of repression by PAX5-PML protein in the differentiation block that leads to the development of acute lymphoblastic leukemia[J].J Biol Chem,2016,291(9):4723-31.
[33]Xue K,Song JZ,Yang Y,et al.PAX5 promotes pre-B cell proliferation by regulating the expression of pre-B cell receptor and its downstream signaling[J].Mol Immunol,2016,73(14):1-9.
[34]Rozovski U,Harris DM,Li P,et al.Constitutive phosphorylation of STAT3 by the CK2-BLNK-CD5 complex[J].Molecul Cancer Res,2017,15(5):610-8.
[35]Gupta N,Delrow J,Drawid A,et al.Repression of B-cell linker(BLNK)and B-cell adaptor for phosphoinositide 3-kinase(BCAP)is important for lymphocyte transformation by Rel proteins[J].Cancer Res,2008,68(3):808-14.
[36]Kuang ZX,Guo L,Li X.Identification of key genes and pathways associated with classical hodgkin lymphoma by bioinformatics analysis[J].Mol Med Rep,2017,16(4):4685-93.
[37]Dilillo DJ,Matsushita T,Tedder TF.B10 cells and regulatory Bcells balance immune responses during inflammation,autoimmunity,and cancer[J].Ann NY Acad Sci,2010,1183(1):38-57.
[38]Tasian SK,Loh ML,Hunger SP.Philadelphia chromosome-like acute lymphoblastic leukemia[J].Blood,2017,130(19):2064-72.
[2]Seda V,Mraz M.B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells[J].Eur J Haematol,2015,94(3):193-205.
[3]Kusuyama J,Ai K,Changhwan S,et al.Spleen tyrosine kinase influences the early stages of multilineage differentiation of bone marrow stromal cell lines by regulating phospholipase C gamma activities[J].J Cell Physiol,2018,233(3):118-29.
[4]Szydlowski M,Jablonska E,Juszczynski P.FOXO1 transcription factor:a critical effector of the PI3K-AKT axis in B-Cell development[J].Int Rev Immunol,2014,33(2):146-57.
[5]Bednarski JJ,Pandey R,Schulte E,et al.RAG-mediated DNAdouble-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals[J].J Experim Med,2016,213(2):209-23.
[6]Abdelrasoul H,Werner M,Setz CS,et al.PI3K induces B-cell development and regulates B cell identity[J].Sci Rep,2018,8(1):1327-36.
[7]Polgarova K,Vaskova M,Fronkova E,et al.Quantitative expression of regulatory and differentiation-related genes in the key steps of human hematopoiesis:The LeukoStage Database[J].Differentiation,2016,91(1/3):19-28.
[8]Woyach JA,Ruppert AS,Guinn D,et al.BTKC481S-Mediated resistance to ibrutinib in chronic lymphocytic leukemia[J].J Clin Oncol,2017,35(13):1437-45.
[9]Ndipagbornchi TG,Mauno V.Simulation of the dynamics of primary immunodeficiencies in B cells[J].Front Immunol,2018,(9):1785-93.
[10]Budzyńska PM,Niemel?M,Sarapulov AV,et al.IRF4 deficiency leads to altered BCR signalling revealed by enhanced PI3Kpathway,decreased SHIP expression and defected cytoskeletal responses[J].Scand J Immunol,2015,82(5):418-28.
[11]Mohammad DK,Nore BF,Gustafsson MO,et al.Protein kinase B(AKT)regulates SYK activity and shuttling through 14-3-3 and importin[J].Intern J Biochem Cell Biol,2016,78(1):63-74.
[12]Poe JC,Jia W,Su H,et al.An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD[J].Blood,2017,130(19):2131-45.
[13]Wang J,Sohn H,Sun G,et al.The autoinhibitory C-terminal SH2domain of phospholipase C-γ2 stabilizes B cell receptor signalosome assembly[J].Sci Signal,2014,7(343):a89-95.
[14]Rao A,Luo C,Hogan PG.Transcription factors of the NFAT family:regulation and function[J].Annu Rev Immunol,1997,15(15):707-47.
[15]Patterson HC,Kraus M,Kim Y,et al.The B cell receptor promotes B cell activation and proliferation through a non-ITAM tyrosine in the Ig alpha cytoplasmic domain[J].Immunity,2006,25(1):55-65.
[16]Tsukada S,Baba Y,Dai W.Btk and BLNK in B cell development[J].Adv Immunol,2001,77(5):123-37.
[17]Imamura Y,Oda A,Katahira T,et al.BLNK binds active H-Ras to promote B cell receptor-mediated capping and ERK activation[J].JBiol Chem,2009,284(15):9804-13.
[18]Chuang HC,Wang X,Tan TH.MAP4K family kinases in immunity and inflammation[J].Adv Immunol,2016,129(3):277-314.
[19]Haniuda K,Fukao S,Kodama T,et al.Autonomous membrane IgEsignaling prevents IgE-memory formation[J].Nat Immunol,2016,17(9):1109-17.
[20]Yang ZY,Robinson MJ,Chen XJ,et al.Regulation of B cell fate by chronic activity of the IgE B cell receptor[J].Elife,2016,(5):21238-46.
[21]Hussain RZ,Hayardeny L,Cravens PC,et al.Immune surveillance of the central nervous system in multiple sclerosis-Relevance for therapy and experimental models[J].J Neuroimmunol,2014,276(1/2):9-17.
[22]金桂花,李雪,藤本学,等.B细胞连接蛋白的表达抑制小鼠实验性自身免疫性脑脊髓炎[J].免疫学杂志,2016(10):848-52.
[23]Ray A,Basu S,Williams CB,et al.A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand[J].J Immunol,2012,188(7):3188-98.
[24]Kamino H,Futamura M,Nakamura Y,et al.B-cell linker protein prevents aneuploidy by inhibiting cytokinesis[J].Cancer Sci,2008,99(12):2444-54.
[25]Abu-Arja RF,Chernin LR,Abusin G,et al.Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia[J].Pediatr Blood Cancer,2015,62(9):1674-6.
[26]Lagresle PC,Millili M,Luce S,et al.The BLNK adaptor protein has a nonredundant role in human B-cell differentiation[J].JAllergy Clin Immunol,2014,134(1):145-56.
[27]Nasereddin A,Shamriz O,Keller B,et al.Enteroviral infection in a patient with BLNK adaptor protein deficiency[J].J Clin Immunol,2015,35(4):356-60.
[28]Nasrullayeva GM,Mammadova VR,Khalilova AV,et al.The novel patient with BLNK gene type of agammaglobulinemia[J].Open Access Library J,2017,4(11):1-7.
[29]Hiratsuka T,Takei Y,Ohmori R,et al.ZFP521 contributes to pre-Bcell lymphomagenesis through modulation of the pre-B-cell receptor signaling pathway[J].Oncogene,2016,35(25):3227-38.
[30]Ez-Enr?EC,Rcenas-L?RA,Hidalgo-Miranda A,et al.Gene expression profiling of acute lymphoblastic leukemia in children with?very early relapse[J].Arch Med Res,2016,47(8):644-55.
[31]Katerndahl CD,Heltemes-Harris LM,Willette MJ,et al.Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival[J].Nat Immunol,2017,18(6):694-705.
[32]Imoto N,Hayakawa F,Kurahashi S,et al.B cell linker protein(BLNK)is a selective target of repression by PAX5-PML protein in the differentiation block that leads to the development of acute lymphoblastic leukemia[J].J Biol Chem,2016,291(9):4723-31.
[33]Xue K,Song JZ,Yang Y,et al.PAX5 promotes pre-B cell proliferation by regulating the expression of pre-B cell receptor and its downstream signaling[J].Mol Immunol,2016,73(14):1-9.
[34]Rozovski U,Harris DM,Li P,et al.Constitutive phosphorylation of STAT3 by the CK2-BLNK-CD5 complex[J].Molecul Cancer Res,2017,15(5):610-8.
[35]Gupta N,Delrow J,Drawid A,et al.Repression of B-cell linker(BLNK)and B-cell adaptor for phosphoinositide 3-kinase(BCAP)is important for lymphocyte transformation by Rel proteins[J].Cancer Res,2008,68(3):808-14.
[36]Kuang ZX,Guo L,Li X.Identification of key genes and pathways associated with classical hodgkin lymphoma by bioinformatics analysis[J].Mol Med Rep,2017,16(4):4685-93.
[37]Dilillo DJ,Matsushita T,Tedder TF.B10 cells and regulatory Bcells balance immune responses during inflammation,autoimmunity,and cancer[J].Ann NY Acad Sci,2010,1183(1):38-57.
[38]Tasian SK,Loh ML,Hunger SP.Philadelphia chromosome-like acute lymphoblastic leukemia[J].Blood,2017,130(19):2064-72.