埃巴病毒潜伏膜蛋白的研究进展
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摘要
埃巴病毒(Epstein-Barr Virus, EBV)是一种在人群中感染率高达90%的γ-疱疹病毒,其感染宿主细胞后常以潜伏形式存在并伴随终生,在一定条件诱导下,由潜伏感染转化为裂解感染,导致多种恶性肿瘤的发生。LMP1和LMP2是EBV编码的重要潜伏膜蛋白,它们锚定于细胞膜脂筏区,通过与宿主细胞内多种信号传递分子如TRAF家族蛋白、Caspase家族蛋白和STAT家族等相互作用,参与细胞内多条信号转导通路,进而影响细胞迁移与凋亡,与淋巴组织增生性疾病和恶性肿瘤的发生有着密切联系。本文阐述了LMP1和LMP2的结构特征,在宿主细胞内的基因表达调控及参与信号转导途径的机制等,旨在推进EBV发病机理研究及疫苗的研发等科研进展。
Epstein-Barr virus(EBV) is a human γ-herpes virus which has an infection rate up to 90% in population. After infecting the host cells, EBV stays latent in the cells for life-long period. Under certain inducement, it will transforms from latent infection into lytic infection, which may trigger genesis of several types of malignant tumors. LMP1 and LMP2, the two key latent membrane proteins encoded by EBV, are anchored in the lipid raft region of the host cell membrane, interacting with signaling molecules, such as families of TRAF, Caspase and STAT. LMP1 and LMP2, involved in many signaling pathways, are considered closely related to lymphoproliferative diseases and tumorigenesis through cell migration and apoptosis. This article summarizes and discusses the structure/function of LMP1 and LMP2, focusing on their roles of gene expression regulation and signal transduction pathways in host cells, aiming to pave road for EBV pathogenesis research and related vaccine R&D.
Epstein-Barr virus(EBV) is a human γ-herpes virus which has an infection rate up to 90% in population. After infecting the host cells, EBV stays latent in the cells for life-long period. Under certain inducement, it will transforms from latent infection into lytic infection, which may trigger genesis of several types of malignant tumors. LMP1 and LMP2, the two key latent membrane proteins encoded by EBV, are anchored in the lipid raft region of the host cell membrane, interacting with signaling molecules, such as families of TRAF, Caspase and STAT. LMP1 and LMP2, involved in many signaling pathways, are considered closely related to lymphoproliferative diseases and tumorigenesis through cell migration and apoptosis. This article summarizes and discusses the structure/function of LMP1 and LMP2, focusing on their roles of gene expression regulation and signal transduction pathways in host cells, aiming to pave road for EBV pathogenesis research and related vaccine R&D.
引文
[1]Tsao S,Tsang C M,To K,et al.The role of Epstein-Barr virus in epithelial malignancies[J].The Journal of Pathology,2015,235(2):323-333
[2]Kempkes B,Robertson E S.Epstein-Barr virus latency:current and future perspectives[J].Curr Opin Virol,2015,14:138-144
[3]Murata T.Regulation of Epstein-Barr virus reactivation from latency[J].Microbiology and Immunology,2014,58(6):307-317
[4]Drop B,Strycharz-Dudziak M,Kliszczewska E,et al.Coinfection with Epstein-Barr virus(EBV),Human Papilloma virus(HPV)and Polyoma BK virus(BKPy V)in laryngeal,oropharyngeal and oral cavity cancer[J].International Journal of Molecular Sciences,2017,18(12):2752
[5]Kutok J L,Wang F.Spectrum of Epstein-Barr virus-associated diseases[J].Annu Rev Pathol,2006,1:375-404
[6]Young L S,Yap L F,Murray P G.Epstein-Barr virus:more than 50years old and still providing surprises[J].Nat Rev Cancer,2016,16(12):789-802
[7]Shair K H Y,Bendt K M,Edwards R H,et al.Epstein-Barr virus-encoded latent membrane protein 1(LMP1)and LMP2Afunction cooperatively to promote carcinoma development in a mouse carcinogenesis model[J].Journal of Virology,2012,86(9):5352-5365
[8]Karlsson Q H,Schelcher C,Verrall E,et al.The reversal of epigenetic silencing of the EBV genome is regulated by viral b ZIP protein[J].Biochem Soc Trans,2008,36(Pt 4):637-639
[9]Li J,Liu X,Liu M,et al.Methylation and expression of Epstein Barr virus latent membrane protein 1,2A and 2B in EBV-associated gastric carcinomas and cell lines[J].Digestive and Liver Disease,2016,48(6):673-680
[10]Dirmeier U,Neuhierl B,Kilger E,et al.Latent membrane protein 1 is critical for efficient growth transformation of human B cells by epstein-barr virus[J].Cancer Res,2003,63(11):2982-2989
[11]Coffin W R,Geiger T R,Martin J M.Transmembrane domains 1 and2 of the latent membrane protein 1 of Epstein-Barr virus contain a lipid raft targeting signal and play a critical role in cytostasis[J].JVirol,2003,77(6):3749-3758
[12]Yasui T,Luftig M,Soni V,et al.Latent infection membrane protein transmembrane FWLY is critical for intermolecular interaction,raft localization,and signaling[J].Proc Natl Acad Sci U S A,2004,101(1):278-283
[13]Wrobel C M,Geiger T R,Nix R N,et al.High molecular weight complex analysis of Epstein Barr virus latent membrane protein 1(LMP-1):structural insights into LMP-1's homo-oligomerization and lipid raft association[J].Virus Research,2013,178(2):314-327
[14]Sample J,Liebowitz D,Kieff E.Two related Epstein-Barr virus membrane proteins are encoded by separate genes[J].J Virol,1989,63(2):933-937
[15]Pang M,Lin K,Peh S.The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A(LMP2A)in latency and cancer[J].Cellular and Molecular Biology Letters,2009,14(2)
[16]Dawson C W,Port R J,Young L S.The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma(NPC)[J].Seminars in Cancer Biology,2012,22(2):144-153
[17]Longnecker R,Kieff E.A second Epstein-Barr virus membrane protein(LMP2)is expressed in latent infection and colocalizes with LMP1[J].J Virol,1990,64(5):2319-2326
[18]Lynch D T,Zimmerman J S,Rowe D T.Epstein-Barr virus latent membrane protein 2B(LMP2B)co-localizes with LMP2A in perinuclear regions in transiently transfected cells[J].J Gen Virol,2002,83(Pt 5):1025-1035
[19]Allen M D,Young L S,Dawson C W.The Epstein-Barr virus-encoded LMP2A and LMP2B proteins promote epithelial cell spreading and motility[J].J Virol,2005,79(3):1789-1802
[20]Rovedo M,Longnecker R.Epstein-Barr virus latent membrane protein 2B(LMP2B)modulates LMP2A activity[J].Journal of Virology,2006,81(1):84-94
[21]Togi S,Hatano Y,Muromoto R,et al.Caspase-dependent cleavage regulates protein levels of Epstein-Barr virus-derived latent membrane protein 1[J].FEBS Lett,2016,590(6):808-818
[22]Aviel S,Winberg G,Massucci M,et al.Degradation of the EpsteinBarr virus latent membrane protein 1(LMP1)by the ubiquitinproteasome pathway[J].Journal of Biological Chemistry,2000,275(31):23491-23499
[23]Kieser A,Sterz K R.The latent membrane protein 1(LMP1)[J].Curr Top Microbiol Immunol,2015,391:119-149
[24]Kung C P,Meckes D G,Raab-Traub N.Epstein-Barr virus LMP1activates EGFR,STAT3,and ERK through effects on PKC[J].Journal of Virology,2011,85(9):4399-4408
[25]Zhang K,Lv D,Li R.B Cell receptor activation and chemical induction trigger Caspase-mediated cleavage of PIAS1 to facilitate Epstein-Barr virus reactivation[J].Cell Reports,2017,21(12):3445-3457
[26]Laux G,Dugrillon F,Eckert C,et al.Identification and characterization of an Epstein-Barr virus nuclear antigen 2-responsive cis element in the bidirectional promoter region of latent membrane protein and terminal protein 2 genes[J].J Virol,1994,68(11):6947-6958
[27]Anderson L J,Longnecker R.An auto-regulatory loop for EBVLMP2A involves activation of Notch[J].Virology,2008,371(2):257-266
[28]Kieser A,Sterz K R.The latent membrane protein 1(LMP1)[J].Curr Top Microbiol Immunol,2015,391:119-149
[29]Cen O,Longnecker R.Latent membrane protein 2(LMP2)[J].Curr Top Microbiol Immunol,2015,391:151-180
[30]邱君瑶,郭武华.UBC9与癌症的研究进展[J].生命的化学,2015(03):301-306
[31]Bentz G L,Whitehurst C B,Pagano J S.Epstein-Barr virus latent membrane protein 1(LMP1)C-terminal-activating region 3contributes to LMP1-mediated cellular migration via its interaction with Ubc9[J].Journal of Virology,2011,85(19):10144-10153
[32]Bentz G L,Moss C R,Whitehurst C B,et al.LMP1-induced sumoylation influences the maintenance of Epstein-Barr virus latency through KAP1[J].Journal of Virology,2015,89(15):7465-7477
[33]Longnecker R,Merchant M,Brown M E,et al.WW-and SH3-domain interactions with Epstein-Barr virus LMP2A[J].Exp Cell Res,2000,257(2):332-340
[34]Engels N,Yigit G K,Emmerich C H,et al.Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B cell antigen receptor-like activation signal[J].Cell Commun Signal,2012,10(1):9
[35]Dykstra M L,Longnecker R,Pierce S K.Epstein-Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR[J].Immunity,2001,14(1):57-67
[36]Ikeda M,Ikeda A,Longan L C,et al.The Epstein-Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases[J].Virology,2000,268(1):178-191
[37]Xu Y,Shi Y,Yuan Q,et al.Epstein-Barr Virus encoded LMP1regulates cyclin D1 promoter activity by nuclear EGFR and STAT3 in CNE1 cells[J].J Exp Clin Cancer Res,2013,32:90
[38]Ontiveros E P,Halwani A,Stunz L L,et al.A new model of LMP1-MYC interaction in B cell lymphoma[J].Leuk Lymphoma,2014,55(12):2917-2923
[39]Zhang J,Jia L,Lin W,et al.Epstein-Barr virus-encoded latent membrane protein 1 upregulates glucose transporter 1 transcription via the mTORC1/NF-kappaB signaling pathways[J].J Virol,2017,91(6)
[40]Moody C A,Scott R S,Amirghahari N,et al.Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A[J].JVirol,2005,79(9):5499-5506
[41]Fish K,Chen J,Longnecker R.Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma[J].Blood,2014,123(4):530-540
[2]Kempkes B,Robertson E S.Epstein-Barr virus latency:current and future perspectives[J].Curr Opin Virol,2015,14:138-144
[3]Murata T.Regulation of Epstein-Barr virus reactivation from latency[J].Microbiology and Immunology,2014,58(6):307-317
[4]Drop B,Strycharz-Dudziak M,Kliszczewska E,et al.Coinfection with Epstein-Barr virus(EBV),Human Papilloma virus(HPV)and Polyoma BK virus(BKPy V)in laryngeal,oropharyngeal and oral cavity cancer[J].International Journal of Molecular Sciences,2017,18(12):2752
[5]Kutok J L,Wang F.Spectrum of Epstein-Barr virus-associated diseases[J].Annu Rev Pathol,2006,1:375-404
[6]Young L S,Yap L F,Murray P G.Epstein-Barr virus:more than 50years old and still providing surprises[J].Nat Rev Cancer,2016,16(12):789-802
[7]Shair K H Y,Bendt K M,Edwards R H,et al.Epstein-Barr virus-encoded latent membrane protein 1(LMP1)and LMP2Afunction cooperatively to promote carcinoma development in a mouse carcinogenesis model[J].Journal of Virology,2012,86(9):5352-5365
[8]Karlsson Q H,Schelcher C,Verrall E,et al.The reversal of epigenetic silencing of the EBV genome is regulated by viral b ZIP protein[J].Biochem Soc Trans,2008,36(Pt 4):637-639
[9]Li J,Liu X,Liu M,et al.Methylation and expression of Epstein Barr virus latent membrane protein 1,2A and 2B in EBV-associated gastric carcinomas and cell lines[J].Digestive and Liver Disease,2016,48(6):673-680
[10]Dirmeier U,Neuhierl B,Kilger E,et al.Latent membrane protein 1 is critical for efficient growth transformation of human B cells by epstein-barr virus[J].Cancer Res,2003,63(11):2982-2989
[11]Coffin W R,Geiger T R,Martin J M.Transmembrane domains 1 and2 of the latent membrane protein 1 of Epstein-Barr virus contain a lipid raft targeting signal and play a critical role in cytostasis[J].JVirol,2003,77(6):3749-3758
[12]Yasui T,Luftig M,Soni V,et al.Latent infection membrane protein transmembrane FWLY is critical for intermolecular interaction,raft localization,and signaling[J].Proc Natl Acad Sci U S A,2004,101(1):278-283
[13]Wrobel C M,Geiger T R,Nix R N,et al.High molecular weight complex analysis of Epstein Barr virus latent membrane protein 1(LMP-1):structural insights into LMP-1's homo-oligomerization and lipid raft association[J].Virus Research,2013,178(2):314-327
[14]Sample J,Liebowitz D,Kieff E.Two related Epstein-Barr virus membrane proteins are encoded by separate genes[J].J Virol,1989,63(2):933-937
[15]Pang M,Lin K,Peh S.The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A(LMP2A)in latency and cancer[J].Cellular and Molecular Biology Letters,2009,14(2)
[16]Dawson C W,Port R J,Young L S.The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma(NPC)[J].Seminars in Cancer Biology,2012,22(2):144-153
[17]Longnecker R,Kieff E.A second Epstein-Barr virus membrane protein(LMP2)is expressed in latent infection and colocalizes with LMP1[J].J Virol,1990,64(5):2319-2326
[18]Lynch D T,Zimmerman J S,Rowe D T.Epstein-Barr virus latent membrane protein 2B(LMP2B)co-localizes with LMP2A in perinuclear regions in transiently transfected cells[J].J Gen Virol,2002,83(Pt 5):1025-1035
[19]Allen M D,Young L S,Dawson C W.The Epstein-Barr virus-encoded LMP2A and LMP2B proteins promote epithelial cell spreading and motility[J].J Virol,2005,79(3):1789-1802
[20]Rovedo M,Longnecker R.Epstein-Barr virus latent membrane protein 2B(LMP2B)modulates LMP2A activity[J].Journal of Virology,2006,81(1):84-94
[21]Togi S,Hatano Y,Muromoto R,et al.Caspase-dependent cleavage regulates protein levels of Epstein-Barr virus-derived latent membrane protein 1[J].FEBS Lett,2016,590(6):808-818
[22]Aviel S,Winberg G,Massucci M,et al.Degradation of the EpsteinBarr virus latent membrane protein 1(LMP1)by the ubiquitinproteasome pathway[J].Journal of Biological Chemistry,2000,275(31):23491-23499
[23]Kieser A,Sterz K R.The latent membrane protein 1(LMP1)[J].Curr Top Microbiol Immunol,2015,391:119-149
[24]Kung C P,Meckes D G,Raab-Traub N.Epstein-Barr virus LMP1activates EGFR,STAT3,and ERK through effects on PKC[J].Journal of Virology,2011,85(9):4399-4408
[25]Zhang K,Lv D,Li R.B Cell receptor activation and chemical induction trigger Caspase-mediated cleavage of PIAS1 to facilitate Epstein-Barr virus reactivation[J].Cell Reports,2017,21(12):3445-3457
[26]Laux G,Dugrillon F,Eckert C,et al.Identification and characterization of an Epstein-Barr virus nuclear antigen 2-responsive cis element in the bidirectional promoter region of latent membrane protein and terminal protein 2 genes[J].J Virol,1994,68(11):6947-6958
[27]Anderson L J,Longnecker R.An auto-regulatory loop for EBVLMP2A involves activation of Notch[J].Virology,2008,371(2):257-266
[28]Kieser A,Sterz K R.The latent membrane protein 1(LMP1)[J].Curr Top Microbiol Immunol,2015,391:119-149
[29]Cen O,Longnecker R.Latent membrane protein 2(LMP2)[J].Curr Top Microbiol Immunol,2015,391:151-180
[30]邱君瑶,郭武华.UBC9与癌症的研究进展[J].生命的化学,2015(03):301-306
[31]Bentz G L,Whitehurst C B,Pagano J S.Epstein-Barr virus latent membrane protein 1(LMP1)C-terminal-activating region 3contributes to LMP1-mediated cellular migration via its interaction with Ubc9[J].Journal of Virology,2011,85(19):10144-10153
[32]Bentz G L,Moss C R,Whitehurst C B,et al.LMP1-induced sumoylation influences the maintenance of Epstein-Barr virus latency through KAP1[J].Journal of Virology,2015,89(15):7465-7477
[33]Longnecker R,Merchant M,Brown M E,et al.WW-and SH3-domain interactions with Epstein-Barr virus LMP2A[J].Exp Cell Res,2000,257(2):332-340
[34]Engels N,Yigit G K,Emmerich C H,et al.Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B cell antigen receptor-like activation signal[J].Cell Commun Signal,2012,10(1):9
[35]Dykstra M L,Longnecker R,Pierce S K.Epstein-Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR[J].Immunity,2001,14(1):57-67
[36]Ikeda M,Ikeda A,Longan L C,et al.The Epstein-Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases[J].Virology,2000,268(1):178-191
[37]Xu Y,Shi Y,Yuan Q,et al.Epstein-Barr Virus encoded LMP1regulates cyclin D1 promoter activity by nuclear EGFR and STAT3 in CNE1 cells[J].J Exp Clin Cancer Res,2013,32:90
[38]Ontiveros E P,Halwani A,Stunz L L,et al.A new model of LMP1-MYC interaction in B cell lymphoma[J].Leuk Lymphoma,2014,55(12):2917-2923
[39]Zhang J,Jia L,Lin W,et al.Epstein-Barr virus-encoded latent membrane protein 1 upregulates glucose transporter 1 transcription via the mTORC1/NF-kappaB signaling pathways[J].J Virol,2017,91(6)
[40]Moody C A,Scott R S,Amirghahari N,et al.Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A[J].JVirol,2005,79(9):5499-5506
[41]Fish K,Chen J,Longnecker R.Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma[J].Blood,2014,123(4):530-540