PI3K-Akt信号通路与病毒感染

摘要/Abstract

摘要： 控制细胞内关键信号传导通路是病毒在感染过程中调控众多细胞功能的一种重要方式。PI3K-Akt是细胞内重要的信号通路, 一些病毒利用该信号通路与宿主免疫系统进行博弈, 进而成功实现对宿主细胞的感染, 胁迫宿主细胞为其复制增殖服务, 并且最终导致宿主生理代谢功能紊乱, 甚至是诱发癌症生成。因此, 了解PI3K-Akt信号通路在病毒感染过程中的调控作用, 对理解一些病毒感染及发病机制, 以及相关病毒疾病的预防和治疗具有重要意义。综述PI3K-Akt信号通路与病毒感染的相关研究进展。

关键词: PI3K-Akt, 病毒, 感染, 免疫, 癌症

Abstract: Many viruses have developed the ability to modulate key signaling pathways, and govern host cell functions to facilitate its proliferation. PI3K-Akt pathway is one of these key pathways which participate in host-pathogen interaction. Viruses take advantage of this pathway to create an environment favourable for its replication, resulting in dysfunction of the host cells, or even carcinogenesis. A thorough study on the roles of PI3K-Akt pathway in virus infection is of great significance to comprehensively understand pathogenesis, prevention and treatment of virus diseases. In this review, we summarize the recent advances in research on the regulation of PI3K-Akt signaling during virus infection.

Key words: PI3K-Akt, Virus Infection, Immunity, Carcinogenesis

刘荣雕, 阮灵伟. PI3K-Akt信号通路与病毒感染[J]. 生物技术通报, 2013, 0(6): 53-62.

Liu Rongdiao, Ruan Lingwei. PI3K-Akt Signaling Pathway and Viral Infection[J]. Biotechnology Bulletin, 2013, 0(6): 53-62.

参考文献

[1] Cooray S. The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival[J]. J Gen Virol, 2004, 85(Pt 5):1065-1076.
[2] Vogt PK, Hart JR, Gymnopoulos M, et al. Phosphatidylinositol 3-kinase:the oncoprotein[J]. Curr Top Microbiol Immunol, 2010, 347:79-104.
[3] Bottomley MJ, Salim K, Panayotou G. Phospholipid-binding protein domains[J]. Biochim Biophys Acta, 1998, 1436(1-2):165-183.
[4] Maehama T, Dixon JE. PTEN:a tumour suppressor that functions as a phospholipid phosphatase[J]. Trends Cell Biol, 1999, 9(4):125-128.
[5] Leslie NR, Downes CP. PTEN:The down side of PI 3-kinase signalling[J]. Cell Signal, 2002, 14(4):285-295.
[6] Bellacosa A, Testa JR, Staal SP, et al. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region[J]. Science, 1991, 254(5029):274-277.
[7] Jones PF, Jakubowicz T, Pitossi FJ, et al. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily[J]. Proc Natl Acad Sci USA, 1991, 88(10):4171-4175.
[8] Staal SP, Hartley JW, Rowe WP. Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma[J]. Proc Natl Acad Sci USA, 1977, 74(7):3065-3067.
[9] Staal SP, Hartley JW. Thymic lymphoma induction by the AKT8 murine retrovirus[J]. J Exp Med, 1988, 167(3):1259-1264.
[10] Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families[J]. Eur J Biochem, 1991, 201(2):475-481.
[11] Calleja V, Alcor D, Laguerre M, et al. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo[J]. PLoS Biol, 2007, 5(4):e95.
[12] Downward J. Mechanisms and consequences of activation of protein kinase B/Akt[J]. Curr Opin Cell Biol, 1998, 10(2):262-267.
[13] Facchinetti V, Ouyang W, Wei H, et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C[J]. EMBO J, 2008, 27(14):1932-1943.
[14] Dunn EF, Connor JH. HijAkt:The PI3K/Akt pathway in virus replication and pathogenesis[J]. Prog Mol Biol Transl Sci, 2012, 106:223-250.
[15] Hahn-Windgassen A, Nogueira V, Chen CC, et al. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity[J]. J Biol Chem, 2005, 280(37):32081-32089.
[16] Robey RB, Hay N. Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis[J]. Semin Cancer Biol, 2009, 19(1):25-31.
[17] Ramaswamy S, Nakamura N, Vazquez F, et al. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway[J]. Proc Natl Acad Sci USA, 1999, 96(5):2110-2115.
[18] Kane LP, Shapiro VS, Stokoe D, et al. Induction of NF-kappaB by the Akt/PKB kinase[J]. Curr Biol, 1999, 9(11):601-604.
[19] Biggs WH 3rd, Meisenhelder J, Hunter T, et al. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1[J]. Proc Natl Acad Sci USA, 1999, 96(13):7421-7426.
[20] Gao X, Zhang Y, Arrazola P, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling[J]. Nat Cell Biol, 2002, 4(9):699-704.
[21] Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism[J]. Cell, 2006, 124(3):471-484.
[22] Marsh M, Helenius A. Virus entry:open sesame[J]. Cell, 2006, 124(4):729-740.
[23] Mercer J, Schelhaas M, Helenius A. Virus entry by endocytosis[J]. Annu Rev Biochem, 2010, 79:803-833.
[24] Schelhaas M. Come in and take your coat off-how host cells provide endocytosis for virus entry[J]. Cell Microbiol, 2010, 12(10):1378-1388.
[25] Saeed MF, Kolokoltsov AA, Freiberg AN, et al. Phosphoinositide-3 kinase-Akt pathway controls cellular entry of Ebola virus[J]. PLoS Pathog, 2008, 4(8):e1000141.
[26] Ehrhardt C, Marjuki H, Wolff T, et al. Bivalent role of the phosphatidylinositol-3-kinase(PI3K)during influenza virus infection and host cell defence[J]. Cell Microbiol, 2006, 8(8):1336-1348.
[27] Izmailyan R, Hsao JC, Chung CS, et al. Integrin beta1 mediates vaccinia virus entry through activation of PI3K/Akt signaling[J]. J Virol, 2012, 86(12):6677-6687.
[28] de Freitas MH, de Oliveira LC, Mugge FL, et al. The interplay between Aracatuba virus and host signaling pathways:role of PI3K/Akt in viral replication[J]. Arch Virol, 2011, 156(10):1775-1785.
[29] Johnson RA, Wang X, Ma XL, et al. Human cytomegalovirus up-regulates the phosphatidylinositol 3-kinase(PI3-K)pathway:inhibition of PI3-K activity inhibits viral replication and virus-induced signaling[J]. J Virol, 2001, 75(13):6022-6032.
[30] Soares JA, Leite FG, Andrade LG, et al. Activation of the PI3K/Akt pathway early during vaccinia and cowpox virus infections is required for both host survival and viral replication[J]. J Virol, 2009, 83(13):6883-6899.
[31] Esfandiarei M, Luo H, Yanagawa B, et al. Protein kinase B/Akt regulates coxsackievirus B3 replication through a mechanism which is not caspase dependent[J]. J Virol, 2004, 78(8):4289-4298.
[32] Esfandiarei M, Suarez A, Amaral A, et al. Novel role for integrin-linked kinase in modulation of coxsackievirus B3 replication and virus-induced cardiomyocyte injury[J]. Circ Res, 2006, 99(4):354-361.
[33] Zhang HM, Yuan J, Cheung P, et al. Overexpression of interferon-gamma-inducible GTPase inhibits coxsackievirus B3-induced apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway and inhibition of viral replication[J]. J Biol Chem, 2003, 278(35):33011-33019.
[34] Shin YK, Liu Q, Tikoo SK, et al. Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation[J]. J Gen Virol, 2007, 88(Pt 3):942-950.
[35] Brydon EW, Smith H, Sweet C. Influenza A virus-induced apoptosis in bronchiolar epithelial(NCI-H292)cells limits pro-inflammatory cytokine release[J]. J Gen Virol, 2003, 84(Pt 9):2389-2400.
[36] Viuff B, Tjornehoj K, Larsen LE, et al. Replication and clearance of respiratory syncytial virus:apoptosis is an important pathway of virus clearance after experimental infection with bovine respiratory syncytial virus[J]. Am J Pathol, 2002, 161(6):2195-2207.
[37] Thomas KW, Monick MM, Staber JM, et al. Respiratory syncytial virus inhibits apoptosis and induces NF-kappa B activity through a phosphatidylinositol 3-kinase-dependent pathway[J]. J Biol Chem, 2002, 277(1):492-501.
[38] Monick MM, Cameron K, Powers LS, et al. Sphingosine kinase mediates activation of extracellular signal-related kinase and Akt by respiratory syncytial virus[J]. Am J Respir Cell Mol Biol, 2004, 30(6):844-852.
[39] Bitko V, Shulyayeva O, Mazumder B, et al. Nonstructural proteins of respiratory syncytial virus suppress premature apoptosis by an NF-kappaB-dependent, interferon-independent mechanism and facilitate virus growth[J]. J Virol, 2007, 81(4):1786-1795.
[40] Groskreutz DJ, Monick MM, Yarovinsky TO, et al. Respiratory syncytial virus decreases p53 protein to prolong survival of airway epithelial cells[J]. J Immunol, 2007, 179(5):2741-2747.
[41] Lindemans CA, Coffer PJ, Schellens IM, et al. Respiratory syncytial virus inhibits granulocyte apoptosis through a phosphatidylinositol 3-kinase and NF-kappaB-dependent mechanism[J]. J Immunol, 2006, 176(9):5529-5537.
[42] Liu Z, Zhang HM, Yuan J, et al. Focal adhesion kinase mediates the interferon-gamma-inducible GTPase-induced phosphatidylinositol 3-kinase/Akt survival pathway and further initiates a positive feedback loop of NF-kappaB activation[J]. Cell Microbiol, 2008, 10(9):1787-1800.
[43] Esfandiarei M, Boroomand S, Suarez A, et al. Coxsackievirus B3 activates nuclear factor kappa B transcription factor via a phosphatidylinositol-3 kinase/protein kinase B-dependent pathway to improve host cell viability[J]. Cell Microbiol, 2007, 9(10):2358-2371.
[44] Cooray S, Jin L, Best JM. The involvement of survival signaling pat-hways in rubella-virus induced apoptosis[J]. Virol J, 2005, 2:1.
[45] Tyler, KL, Nathanson N. Pathogenesis of viral infections[M]. // Knipe DM, Howley PM. Fields Virology, 4th ed. Philadelphia:Lippincott Williams and Wilkins, 2001:199-244.
[46] Kieff E, Rickinson AB. Epstein-Barr virus and its replication[M]. //Knipe DM, Howley PM. Fields Virology, 4th ed. Philadelphia:Lippincott Williams and Wilkins, 2001:2511-2574.
[47] Dawson CW, Tramountanis G, Eliopoulos AG, et al. Epstein-Barr virus latent membrane protein 1(LMP1)activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodeling[J]. J Biol Chem, 2003, 278(6):3694-3704.
[48] Hatton O, Phillips LK, Vaysberg M, et al. Syk activation of phosphatidylinositol 3-kinase/Akt prevents HtrA2-dependent loss of X-linked inhibitor of apoptosis protein(XIAP)to promote survival of Epstein-Barr virus+(EBV+)B cell lymphomas[J]. J Biol Chem, 2011, 286(43):37368-37378.
[49] Portis T, Longnecker R. Epstein-Barr virus(EBV)LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway[J]. Oncogene, 2004, 23(53):8619-8628.
[50] Fukuda M, Longnecker R. Latent membrane protein 2A inhibits transforming growth factor-beta 1-induced apoptosis through the phosphatidylinositol 3-kinase/Akt pathway[J]. J Virol, 2004, 78(4):1697-1705.
[51] Li X, Chen S, Sun R. Cdk1 Inhibition induces mutually inhibitory apoptosis and reactivation of Kaposi’s sarcoma-associated herpesvirus[J]. J Virol, 2012, 86(12):6668-6676.
[52] Lee H, Veazey R, Williams K, et al. Deregulation of cell growth by the K1 gene of Kaposi’s sarcoma-associated herpesvirus[J]. Nat Med, 1998, 4(4):435-440.
[53] Tomlinson CC, Damania B. The K1 protein of Kaposi’s sarcoma-associated herpesvirus activates the Akt signaling pathway[J]. J Virol, 2004, 78(4):1918-1927.
[54] Wang L, Dittmer DP, Tomlinson CC, et al. Immortalization of primary endothelial cells by the K1 protein of Kaposi’s sarcoma-associated herpesvirus[J]. Cancer Res, 2006, 66(7):3658-3666.
[55] Fothergill T, McMillan NA. Papillomavirus virus-like particles activate the PI3-kinase pathway via alpha-6 beta-4 integrin upon binding[J]. Virology, 2006, 352(2):319-328.
[56] Pim D, Massimi P, Dilworth SM, et al. Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A[J]. Oncogene, 2005, 24(53):7830-7838.
[57] Contreras-Paredes A, De la Cruz-Hernandez E, Martinez-Ramirez I, et al. E6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3-kinase(akt/PI3K)signaling pathway[J]. Virology, 2009, 383(1):78-85.
[58] Zhang B, Spandau DF, Roman A. E5 protein of human papillomav-irus type 16 protects human foreskin keratinocytes from UV B-irra-diation-induced apoptosis[J]. J Virol, 2002, 76(1):220-231.
[59] Whitman M, Kaplan DR, Schaffhausen B, et al. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation[J]. Nature, 1985, 315(6016):239-242.
[60] Dahl J, Jurczak A, Cheng LA, et al. Evidence of a role for phosphatidylinositol 3-kinase activation in the blocking of apoptosis by polyomavirus middle T antigen[J]. J Virol, 1998, 72(4):3221-3226.
[61] Kang-Park S, Im JH, Lee JH, et al. PTEN modulates hepatitis B virus-X protein induced survival signaling in Chang liver cells[J]. Virus Res, 2006, 122(1-2):53-60.
[62] Lee YI, Kang-Park S, Do SI. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade[J]. J Biol Chem, 2001, 276(20):16969-16977.
[63] Shih WL, Kuo ML, Chuang SE, et al. Hepatitis B virus X protein inhibits transforming growth factor-beta -induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway[J]. J Biol Chem, 2000, 275(33):25858-25864.
[64] Shih WL, Kuo ML, Chuang SE, et al. Hepatitis B virus X protein activates a survival signaling by linking SRC to phosphatidylinositol 3-kinase[J]. J Biol Chem, 2003, 278(34):31807-31813.
[65] Barreiros AP, Sprinzl M, Rosset S, et al. EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes[J]. Int J Cancer, 2009, 124(1):120-129.
[66] Mannova P, Beretta L. Activation of the N-Ras-PI3K-Akt-mTOR pathway by hepatitis C virus:control of cell survival and viral replication[J]. J Virol, 2005, 79(14):8742-8749.
[67] Pei R, Chen H, Lu L, et al. Hepatitis C virus infection induces the expression of amphiregulin, a factor related to the activation of cellular survival pathways and required for efficient viral assembly[J]. J Gen Virol, 2011, 92(Pt 10):2237-2248.
[68] Jahan S, Khaliq S, Siddiqi MH, et al. Anti-apoptotic effect of HCV core gene of genotype 3a in Huh-7 cell line[J]. Virol J, 2011, 8:522.
[69] Milward A, Mankouri J, Harris M. Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion[J]. J Gen Virol, 2010, 91(Pt 2):373-381.
[70] Street A, Macdonald A, McCormick C, et al. Hepatitis C virus NS5A-mediated activation of phosphoinositide 3-kinase results in stabilization of cellular beta-catenin and stimulation of beta-catenin-responsive transcription[J]. J Virol, 2005, 79(8):5006-5016.
[71] Fuerer C, Nusse R, Ten Berge D. Wnt signalling in development and disease. max delbrück center for molecular medicine meeting on Wnt signaling in development and disease[J]. EMBO Rep, 2008, 9(2):134-138.
[72] Chen J, Hu CF, Hou JH, et al. Epstein-Barr virus encoded latent membrane protein 1 regulates mTOR signaling pathway genes which predict poor prognosis of nasopharyngeal carcinoma[J]. J Transl Med, 2010, 8:30.
[73] Moody CA, Scott RS, Amirghahari N, et al. Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A[J]. J Virol, 2005, 79(9):5499-5506.
[74] Carracedo A, Pandolfi PP. The PTEN-PI3K pathway:of feedbacks and cross-talks[J]. Oncogene, 2008, 27(41):5527-5541.
[75] Chung TW, Lee YC, Ko JH, et al. Hepatitis B Virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells[J]. Cancer Res, 2003, 63(13):3453-3458.
[76] Clement S, Peyrou M, Sanchez-Pareja A, et al. Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets[J]. Hepatology, 2011, 54(1):38-49.
[77] Collins K, Jacks T, Pavletich NP. The cell cycle and cancer[J]. Proc Natl Acad Sci USA, 1997, 94(7):2776-2778.
[78] Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle:a review of regulation, deregulation and therapeutic targets in cancer[J]. Cell Prolif, 2003, 36(3):131-149.
[79] Chin R, Earnest-Silveira L, Koeberlein B, et al. Modulation of MAPK pathways and cell cycle by replicating hepatitis B virus:factors contributing to hepatocarcinogenesis[J]. J Hepatol, 2007, 47(3):325-337.
[80] Liu H, Xu J, Zhou L, et al. Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3K/Akt pathway[J]. Cancer Res, 2011, 71(24):7547-7557.
[81] Kong G, Zhang J, Zhang S, et al. Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model[J]. PLoS One, 2011, 6(5):e19518.
[82] Charette ST, McCance DJ. The E7 protein from human papilloma-virus type 16 enhances keratinocyte migration in an Akt-dependent manner[J]. Oncogene, 2007, 26(52):7386-7390.
[83] Bjornholm M, Zierath JR. Insulin signal transduction in human skeletal muscle:identifying the defects in Type II diabetes[J]. Biochem Soc Trans, 2005, 33(Pt 2):354-357.
[84] Riley JK, Carayannopoulos MO, Wyman AH, et al. Phosphatidylin-ositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts[J]. J Biol Chem, 2006, 281(9):6010-6019.
[85] Banerjee S, Saito K, Ait-Goughoulte M, et al. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance[J]. J Virol, 2008, 82(6):2606-2612.
[86] Del Campo JA, Romero-Gómenzm M. Steatosis and insulin resist-ance in hepatitis C:a way out for the virus?[J] . World J Gastro-enterol, 2009, 15(40):5014.
[87] Young AT, Dahl J, Hausdorff SF, et al. Phosphatidylinositol 3-kinase binding to polyoma virus middle tumor antigen mediates elevation of glucose transport by increasing translocation of the GLUT1 transporter[J]. Proc Natl Acad Sci USA, 1995, 92(25):11613-11617.
[88] Kaur S, Katsoulidis E, Platanias LC. Akt and mRNA translation by interferons[J]. Cell Cycle, 2008, 7(14):2112-2116.
[89] Kaur S, Sassano A, Dolniak B, et al. Role of the Akt pathway in mRNA translation of interferon-stimulated genes[J]. Proc Natl Acad Sci USA, 2008, 105(12):4808-4813.
[90] Kaur S, Sassano A, Joseph AM, et al. Dual regulatory roles of phosphatidylinositol 3-kinase in IFN signaling[J]. J Immunol, 2008, 181(10):7316-7323.
[91] Lin PY, Liu HJ, Liao MH, et al. Activation of PI 3-kinase/Akt/NF-kappaB and Stat3 signaling by avian reovirus S1133 in the early stages of infection results in an inflammatory response and delayed apoptosis[J]. Virology, 2010, 400(1):104-114.
[92] Mastronarde JG, He B, Monick MM, et al. Induction of interleukin(IL)-8 gene expression by respiratory syncytial virus involves activation of nuclear factor(NF)-kappa B and NF-IL-6[J]. J Infect Dis, 1996, 174(2):262-267.
[93] Mastronarde JG, Monick MM, Hunninghake GW. Oxidant tone regulates IL-8 production in epithelium infected with respiratory syncytial virus[J]. Am J Respir Cell Mol Biol, 1995, 13(2):237-244.
[94] Freudenburg W, Moran JM, Lents NH, et al. Phosphatidylinositol 3-kinase regulates macrophage responses to double-stranded RNA and encephalomyocarditis virus[J]. J Innate Immun, 2010, 2(1):77-86.
[95] Guillot L, Le Goffic R, Bloch S, et al. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus[J]. J Biol Chem, 2005, 280(7):5571-5580.
[96] Tyner JW, Uchida O, Kajiwara N, et al. CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection[J]. Nat Med, 2005, 11(11):1180-1187.
[97] Carsillo M, Kim D, Niewiesk S. Role of AKT kinase in measles virus replication[J]. J Virol, 2010, 84(4):2180-2183.
[98] Huang Y, Erdmann N, Peng H, et al. TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation[J]. J Immunol, 2006, 177(4):2304-2313.
[99] Cui M, Huang Y, Zhao Y, et al. Transcription factor FOXO3a mediates apoptosis in HIV-1-infected macrophages[J]. J Immunol, 2008, 180(2):898-906.
[100] Mohankumar V, Dhanushkodi NR, Raju R. Sindbis virus replication, is insensitive to rapamycin and torin1, and suppresses Akt/mTOR pathway late during infection in HEK cells[J]. Biochem Biophys Res Commun, 2011, 406(2):262-267.
[101] Peng JM, Liang SM, Liang CM. VP1 of foot-and-mouth disease virus induces apoptosis via the Akt signaling pathway[J]. J Biol Chem, 2004, 279(50):52168-52174