For best viewing of the website please use Mozilla Firefox or Google Chrome.
Citation: Xueyu Wang, Zhiqiang Wei, Yongfang Jiang, Zhongji Meng, Mengji Lu. mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication [J].VIROLOGICA SINICA, 2021, 36(6) : 1303-1314.

mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication

  • Corresponding author: Zhongji Meng,, ORCID: 0000-0003-0401-535X
    Mengji Lu,, ORCID: 0000-0003-4287-9941
  • Received Date: 05 May 2021
    Accepted Date: 24 August 2021
    Published Date: 28 September 2021
    Available online: 01 December 2021
  • Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that includes mTOR complex (mTORC) 1 and mTORC2. The mTOR pathway is activated in viral hepatitis, including hepatitis B virus (HBV) infection-induced hepatitis. Currently, chronic HBV infection remains one of the most serious public health issues worldwide. The unavailability of effective therapeutic strategies for HBV suggests that clarification of the pathogenesis of HBV infection is urgently required. Increasing evidence has shown that HBV infection can activate the mTOR pathway, indicating that HBV utilizes or hijacks the mTOR pathway to benefit its own replication. Therefore, the mTOR signaling pathway might be a crucial target for controlling HBV infection. Here, we summarize and discuss the latest findings from model biology research regarding the interaction between the mTOR signaling pathway and HBV replication.

  • 加载中
    1. Araki K, Youngblood B, Ahmed R (2010) The role of mTOR in memory CD8 T-cell differentiation. Immunol Rev 235: 234-243
        doi: 10.1111/j.0105-2896.2010.00898.x

    2. Betz C, Hall MN (2013) Where is mTOR and what is it doing there? J Cell Biol 203: 563-574
        doi: 10.1083/jcb.201306041

    3. Bossler F, Hoppe-Seyler K, Hoppe-Seyler F (2019) PI3K/AKT/mTOR signaling regulates the virus/host cell crosstalk in HPV-positive cervical cancer cells. Int J Mol Sci 20: 2188
        doi: 10.3390/ijms20092188

    4. Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A, Murthy N, Pulendran B (2008) Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 9: 1157-1164
        doi: 10.1038/ni.1645

    5. Cha MY, Kim CM, Park YM, Ryu WS (2004) Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology 39: 1683-1693
        doi: 10.1002/hep.20245

    6. Chan C, Thurnherr T, Wang J, Gallart-Palau X, Sze SK, Rozen S, Lee CG (2016) Global re-wiring of p53 transcription regulation by the hepatitis B virus X protein. Mol Oncol 10: 1183-1195
        doi: 10.1016/j.molonc.2016.05.006

    7. Chan C, Wang Y, Chow PK, Chung AY, Ooi LL, Lee CG (2013) Altered binding site selection of p53 transcription cassettes by hepatitis B virus X protein. Mol Cell Biol 33: 485-497
        doi: 10.1128/MCB.01189-12

    8. Chen M, Lu J, Wei W, Lv Y, Zhang X, Yao Y, Wang L, Ling T, Zou X (2018) Effects of proton pump inhibitors on reversing multidrug resistance via downregulating V-ATPases/PI3K/Akt/mTOR/HIF-1alpha signaling pathway through TSC1/2 complex and Rheb in human gastric adenocarcinoma cells in vitro and in vivo. Onco Targets Ther 11: 6705-6722
        doi: 10.2147/OTT.S161198

    9. Chen X, Hu Y, Zhang W, Chen K, Hu J, Li X, Liang L, Cai X, Hu J, Wang K, Huang A, Tang N (2019) Cisplatin induces autophagy to enhance hepatitis B virus replication via activation of ROS/JNK and inhibition of the Akt/mTOR pathway. Free Radic Biol Med 131: 225-236
        doi: 10.1016/j.freeradbiomed.2018.12.008

    10. Cheng X, Wang Y, Tian J, Zhou L, Chen X, Guo H, Zeng J, Shen N, Li J, Ke J, Zhu Y, Gong J, Chang J, Liu L, Zhong R (2019) SLC10A1 S267F variant influences susceptibility to HBV infection and reduces cholesterol level by impairing bile acid uptake. J Viral Hepat 26: 1178-1185
        doi: 10.1111/jvh.13157

    11. Choi YM, Lee SY, Kim BJ (2019) Naturally occurring hepatitis B virus mutations leading to endoplasmic reticulum stress and their contribution to the progression of hepatocellular carcinoma. Int J Mol Sci 20: 597
        doi: 10.3390/ijms20030597

    12. Chung TW, Lee YC, Kim CH (2004) Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J 18: 1123-1125
        doi: 10.1096/fj.03-1429fje

    13. Chung TW, Lee YC, Ko JH, Kim CH (2003) Hepatitis B Virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells. Cancer Res 63: 3453-3458

    14. Ciuffreda L, Di Sanza C, Incani UC, Milella M (2010) The mTOR pathway: a new target in cancer therapy. Curr Cancer Drug Targets 10: 484-495
        doi: 10.2174/156800910791517172

    15. Claus C, Liebert UG (2014) A renewed focus on the interplay between viruses and mitochondrial metabolism. Arch Virol 159: 1267-1277
        doi: 10.1007/s00705-013-1841-1

    16. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450: 736-740
        doi: 10.1038/nature06322

    17. Daud M, Rana MA, Husnain T, Ijaz B (2017) Modulation of Wnt signaling pathway by hepatitis B virus. Arch Virol 162: 2937-2947
        doi: 10.1007/s00705-017-3462-6

    18. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30: 832-844
        doi: 10.1016/j.immuni.2009.04.014

    19. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12: 295-303

    20. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39: 171-183
        doi: 10.1016/j.molcel.2010.06.022

    21. Eaton HE, Saffran HA, Wu FW, Quach K, Smiley JR (2014) Herpes simplex virus protein kinases US3 and UL13 modulate VP11/12 phosphorylation, virion packaging, and phosphatidylinositol 3-kinase/Akt signaling activity. J Virol 88: 7379-7388
        doi: 10.1128/JVI.00712-14

    22. Efeyan A, Zoncu R, Sabatini DM (2012) Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med 18: 524-533
        doi: 10.1016/j.molmed.2012.05.007

    23. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294: 1942-1945
        doi: 10.1126/science.1066015

    24. Fanning GC, Zoulim F, Hou J, Bertoletti A (2019) Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat Rev Drug Discov 18: 827-844
        doi: 10.1038/s41573-019-0037-0

    25. Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102: 8204-8209
        doi: 10.1073/pnas.0502857102

    26. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39: D945-950
        doi: 10.1093/nar/gkq929

    27. Geier A (2014) Hepatitis B virus: the "metabolovirus" highjacks cholesterol and bile acid metabolism. Hepatology 60: 1458-1460
        doi: 10.1002/hep.27224

    28. Gish RG, Given BD, Lai CL, Locarnini SA, Lau JY, Lewis DL, Schluep T (2015) Chronic hepatitis B: virology, natural history, current management and a glimpse at future opportunities. Antiviral Res 121: 47-58
        doi: 10.1016/j.antiviral.2015.06.008

    29. Glebe D, Bremer CM (2013) The molecular virology of hepatitis B virus. Semin Liver Dis 33: 103-112
        doi: 10.1055/s-0033-1345717

    30. Groenewoud MJ, Zwartkruis FJ (2013) Rheb and Rags come together at the lysosome to activate mTORC1. Biochem Soc Trans 41: 951-955
        doi: 10.1042/BST20130037

    31. Guo H, Jiang D, Zhou T, Cuconati A, Block TM, Guo JT (2007a) Characterization of the intracellular deproteinized relaxed circular DNA of hepatitis B virus: an intermediate of covalently closed circular DNA formation. J Virol 81: 12472-12484
        doi: 10.1128/JVI.01123-07

    32. Guo H, Zhou T, Jiang D, Cuconati A, Xiao GH, Block TM, Guo JT (2007b) Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-akt signal transduction pathway. J Virol 81: 10072-10080
        doi: 10.1128/JVI.00541-07

    33. Guo Z, Cheng X, Feng X, Zhao K, Zhang M, Yao R, Chen Y, Wang Y, Hao H, Wang Z (2019) The mTORC1/4EBP1/PPARgamma axis mediates insulin-induced lipogenesis by regulating lipogenic gene expression in bovine mammary epithelial cells. J Agric Food Chem 67: 6007-6018
        doi: 10.1021/acs.jafc.9b01411

    34. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30: 214-226
        doi: 10.1016/j.molcel.2008.03.003

    35. Han J, Li E, Chen L, Zhang Y, Wei F, Liu J, Deng H, Wang Y (2015) The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524: 243-246
        doi: 10.1038/nature14557

    36. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18: 1926-1945
        doi: 10.1101/gad.1212704

    37. He L, Zang A, Du M, Ma D, Yuan C, Zhou C, Mu J, Shi H, Li D, Huang X, Deng Q, Xiao J, Yan H, Hui L, Lan K, Xiong S, Li X, Huang Z, Xiao H (2015) mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines. Virol Sin 30: 174-189
        doi: 10.1007/s12250-015-3606-3

    38. He Q, Song X, Huang Y, Huang W, Ye B, Luo H, Luo H, Wu L, Wang Z, Chen W, Zhang L (2018) Dexamethasone stimulates hepatitis B virus (HBV) replication through autophagy. Med Sci Monit 24: 4617-4624
        doi: 10.12659/MSM.906250

    39. Huang W, Zhao F, Huang Y, Li X, Zhu S, Hu Q, Chen W (2014) Rapamycin enhances HBV production by inducing cellular autophagy. Hepat Mon 14: e20719

    40. Hung JH, Su IJ, Lei HY, Wang HC, Lin WC, Chang WT, Huang W, Chang WC, Chang YS, Chen CC, Lai MD (2004) Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase. J Biol Chem 279: 46384-46392
        doi: 10.1074/jbc.M403568200

    41. Inoki K, Li Y, Xu T, Guan KL (2003a) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17: 1829-1834
        doi: 10.1101/gad.1110003

    42. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126: 955-968
        doi: 10.1016/j.cell.2006.06.055

    43. Inoki K, Zhu T, Guan KL (2003b) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115: 577-590
        doi: 10.1016/S0092-8674(03)00929-2

    44. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122-1128
        doi: 10.1038/ncb1183

    45. Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104: 12017-12022
        doi: 10.1073/pnas.0705070104

    46. Ji WT, Liu HJ (2008) PI3K-Akt signaling and viral infection. Recent Pat Biotechnol 2: 218-226
        doi: 10.2174/187220808786241042

    47. Karayiannis P (2017) Hepatitis B virus: virology, molecular biology, life cycle and intrahepatic spread. Hepatol Int 11: 500-508
        doi: 10.1007/s12072-017-9829-7

    48. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110: 163-175
        doi: 10.1016/S0092-8674(02)00808-5

    49. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13: 132-141
        doi: 10.1038/ncb2152

    50. Kim K, Kim KH, Kim HH, Cheong J (2008) Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRalpha. Biochem J 416: 219-230
        doi: 10.1042/BJ20081336

    51. Kim KH, Shin HJ, Kim K, Choi HM, Rhee SH, Moon HB, Kim HH, Yang US, Yu DY, Cheong J (2007) Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma. Gastroenterology 132: 1955-1967
        doi: 10.1053/j.gastro.2007.03.039

    52. Kock J, Rosler C, Zhang JJ, Blum HE, Nassal M, Thoma C (2010) Generation of covalently closed circular DNA of hepatitis B viruses via intracellular recycling is regulated in a virus specific manner. PLoS Pathog 6: e1001082
        doi: 10.1371/journal.ppat.1001082

    53. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149: 274-293
        doi: 10.1016/j.cell.2012.03.017

    54. Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei Y, Sun HL, Li LY, Ping B, Huang WC, He X, Hung JY, Lai CC, Ding Q, Su JL, Yang JY, Sahin AA, Hortobagyi GN, Tsai FJ, Tsai CH, Hung MC (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130: 440-455
        doi: 10.1016/j.cell.2007.05.058

    55. Lee JO, Kwun HJ, Jung JK, Choi KH, Min DS, Jang KL (2005) Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 24: 6617-6625
        doi: 10.1038/sj.onc.1208827

    56. Lee SG, Rho HM (2000) Transcriptional repression of the human p53 gene by hepatitis B viral X protein. Oncogene 19: 468-471
        doi: 10.1038/sj.onc.1203312

    57. Lekmine F, Sassano A, Uddin S, Smith J, Majchrzak B, Brachmann SM, Hay N, Fish EN, Platanias LC (2004) Interferon-gamma engages the p70 S6 kinase to regulate phosphorylation of the 40S S6 ribosomal protein. Exp Cell Res 295: 173-182
        doi: 10.1016/j.yexcr.2003.12.021

    58. Li H, Zhu W, Zhang L, Lei H, Wu X, Guo L, Chen X, Wang Y, Tang H (2015) The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment. Sci Rep 5: 8421
        doi: 10.1038/srep08421

    59. Li J, Liu Y, Wang Z, Liu K, Wang Y, Liu J, Ding H, Yuan Z (2011) Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J Virol 85: 6319-6333
        doi: 10.1128/JVI.02627-10

    60. Li Z, Xu G, Qin Y, Zhang C, Tang H, Yin Y, Xiang X, Li Y, Zhao J, Mulholland M, Zhang W (2014) Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARgamma signaling pathway. Proc Natl Acad Sci U S A 111: 13163-13168
        doi: 10.1073/pnas.1411571111

    61. Liang TJ, Block TM, McMahon BJ, Ghany MG, Urban S, Guo JT, Locarnini S, Zoulim F, Chang KM, Lok AS (2015) Present and future therapies of hepatitis B: from discovery to cure. Hepatology 62: 1893-1908
        doi: 10.1002/hep.28025

    62. Lin Y, Deng W, Pang J, Kemper T, Hu J, Yin J, Zhang J, Lu M (2017) The microRNA-99 family modulates hepatitis B virus replication by promoting IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced autophagy. Cell Microbiol.
        doi: 10.1111/cmi.12709

    63. Lin Y, Wu C, Wang X, Kemper T, Squire A, Gunzer M, Zhang J, Chen X, Lu M (2019a) Hepatitis B virus is degraded by autophagosome-lysosome fusion mediated by Rab7 and related components. Protein Cell 10: 60-66
        doi: 10.1007/s13238-018-0555-2

    64. Lin Y, Wu C, Wang X, Liu S, Kemper T, Li F, Squire A, Zhu Y, Zhang J, Chen X, Lu M (2019b) Synaptosomal-associated protein 29 is required for the autophagic degradation of hepatitis B virus. FASEB J 33: 6023-6034
        doi: 10.1096/fj.201801995RR

    65. Lin Y, Wu C, Wang X, Liu S, Zhao K, Kemper T, Yu H, Li M, Zhang J, Chen M, Zhu Y, Chen X, Lu M (2019c) Glucosamine promotes hepatitis B virus replication through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling. Autophagy 16: 568-516 Article

    66. Lin Y, Zhao Z, Huang A, Lu M (2020) Interplay between cellular autophagy and hepatitis B virus replication: a systematic review. Cells 9: 2101
        doi: 10.3390/cells9092101

    67. Liu B, Fang M, He Z, Cui D, Jia S, Lin X, Xu X, Zhou T, Liu W (2015) Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation. Cell Death Dis 6: e1980
        doi: 10.1038/cddis.2015.322

    68. Liu H, Xu J, Zhou L, Yun X, Chen L, Wang S, Sun L, Wen Y, Gu J (2011) Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3K/Akt pathway. Cancer Res 71: 7547-7557
        doi: 10.1158/0008-5472.CAN-11-2260

    69. Liu Y, Zhang DT, Liu XG (2015) mTOR signaling in T cell immunity and autoimmunity. Int Rev Immunol 34: 50-66
        doi: 10.3109/08830185.2014.933957

    70. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121: 179-193
        doi: 10.1016/j.cell.2005.02.031

    71. Mehta A, Lu X, Block TM, Blumberg BS, Dwek RA (1997) Hepatitis B virus (HBV) envelope glycoproteins vary drastically in their sensitivity to glycan processing: evidence that alteration of a single N-linked glycosylation site can regulate HBV secretion. Proc Natl Acad Sci U S A 94: 1822-1827
        doi: 10.1073/pnas.94.5.1822

    72. Na TY, Shin YK, Roh KJ, Kang SA, Hong I, Oh SJ, Seong JK, Park CK, Choi YL, Lee MO (2009) Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 49: 1122-1131
        doi: 10.1002/hep.22740

    73. Nassal M (2015) HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64: 1972-1984
        doi: 10.1136/gutjnl-2015-309809

    74. Oehler N, Volz T, Bhadra OD, Kah J, Allweiss L, Giersch K, Bierwolf J, Riecken K, Pollok JM, Lohse AW, Fehse B, Petersen J, Urban S, Lutgehetmann M, Heeren J, Dandri M (2014) Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology 60: 1483-1493
        doi: 10.1002/hep.27159

    75. Patman G (2014) Hepatitis: HBV infection alters bile acid metabolism gene profile. Nat Rev Gastroenterol Hepatol 11: 332

    76. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460: 103-107
        doi: 10.1038/nature08097

    77. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146: 408-420
        doi: 10.1016/j.cell.2011.06.034

    78. Ranadheera C, Coombs KM, Kobasa D (2018) Comprehending a killer: the Akt/mTOR signaling pathways are temporally high-jacked by the highly pathogenic 1918 Influenza Virus. EBioMedicine 32: 142-163
        doi: 10.1016/j.ebiom.2018.05.027

    79. Raney AK, Johnson JL, Palmer CN, McLachlan A (1997) Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter. J Virol 71: 1058-1071
        doi: 10.1128/jvi.71.2.1058-1071.1997

    80. Rawat S, Bouchard MJ (2015) The hepatitis B virus (HBV) HBx protein activates AKT to simultaneously regulate HBV replication and hepatocyte survival. J Virol 89: 999-1012
        doi: 10.1128/JVI.02440-14

    81. Reese V, Ondracek C, Rushing C, Li L, Oropeza CE, McLachlan A (2011) Multiple nuclear receptors may regulate hepatitis B virus biosynthesis during development. Int J Biochem Cell Biol 43: 230-237
        doi: 10.1016/j.biocel.2009.11.016

    82. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A 101: 13489-13494
        doi: 10.1073/pnas.0405659101

    83. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296-1302
        doi: 10.1016/j.cub.2004.06.054

    84. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098-1101
        doi: 10.1126/science.1106148

    85. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168: 960-976
        doi: 10.1016/j.cell.2017.02.004

    86. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20: 51-56
        doi: 10.1016/j.gde.2009.10.009

    87. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM (2010) mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468: 1100-1104
        doi: 10.1038/nature09584

    88. Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15: 155-162
        doi: 10.1038/nrm3757

    89. Shin HJ, Park YH, Kim SU, Moon HB, Park DS, Han YH, Lee CH, Lee DS, Song IS, Lee DH, Kim M, Kim NS, Kim DG, Kim JM, Kim SK, Kim YN, Kim SS, Choi CS, Kim YB, Yu DY (2011) Hepatitis B virus X protein regulates hepatic glucose homeostasis via activation of inducible nitric oxide synthase. J Biol Chem 286: 29872-29881
        doi: 10.1074/jbc.M111.259978

    90. Shlomai A, Paran N, Shaul Y (2006) PGC-1alpha controls hepatitis B virus through nutritional signals. Proc Natl Acad Sci U S A 103: 16003-16008
        doi: 10.1073/pnas.0607837103

    91. Shlomai A, Shaul Y (2009) The metabolic activator FOXO1 binds hepatitis B virus DNA and activates its transcription. Biochem Biophys Res Commun 381: 544-548
        doi: 10.1016/j.bbrc.2009.02.078

    92. Sigrid Schmitt DG, Alving K, Tolle TK, Linder M, Geyer H, Linder D, Peter-Katalinic J, Gerlich WH, Geyeri R (1999) Analysis of the Pre-S2 N- and O-linked glycans of the M surface protein from human hepatitis B virus. J Biol Chem 274: 11945-11957
        doi: 10.1074/jbc.274.17.11945

    93. Sir D, Tian Y, Chen WL, Ann DK, Yen TS, Ou JH (2010) The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci U S A 107: 4383-4388
        doi: 10.1073/pnas.0911373107

    94. Subic M, Zoulim F (2018) How to improve access to therapy in hepatitis B patients. Liver Int 38(Suppl 1): 115-121

    95. Tang LSY, Covert E, Wilson E, Kottilil S (2018) Chronic hepatitis B infection: A review. JAMA 319: 1802-1813
        doi: 10.1001/jama.2018.3795

    96. Tarn C, Lee S, Hu Y, Ashendel C, Andrisani OM (2001) Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes. J Biol Chem 276: 34671-34680
        doi: 10.1074/jbc.M104105200

    97. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13: 1259-1268
        doi: 10.1016/S0960-9822(03)00506-2

    98. Teng CF, Hsieh WC, Wu HC, Lin YJ, Tsai HW, Huang W, Su IJ (2015a) Hepatitis B virus pre-S2 mutant induces aerobic glycolysis through mammalian target of rapamycin signal cascade. PLoS ONE 10: e0122373
        doi: 10.1371/journal.pone.0122373

    99. Teng CF, Wu HC, Hsieh WC, Tsai HW, Su IJ (2015b) Activation of ATP citrate lyase by mTOR signal induces disturbed lipid metabolism in hepatitis B virus pre-S2 mutant tumorigenesis. J Virol 89: 605-614
        doi: 10.1128/JVI.02363-14

    100. Teng CF, Wu HC, Tsai HW, Shiah HS, Huang W, Su IJ (2011) Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy. Hepatology 54: 1199-1207
        doi: 10.1002/hep.24529

    101. Tian Y, Sir D, Kuo CF, Ann DK, Ou JH (2011) Autophagy required for hepatitis B virus replication in transgenic mice. J Virol 85: 13453-13456
        doi: 10.1128/JVI.06064-11

    102. Tong S, Revill P (2016) Overview of hepatitis B viral replication and genetic variability. J Hepatol 64: S4-16
        doi: 10.1016/j.jhep.2016.01.027

    103. Uddin S, Yenush L, Sun XJ, Sweet ME, White MF, Platanias LC (1995) Interferon-alpha engages the insulin receptor substrate-1 to associate with the phosphatidylinositol 3'-kinase. J Biol Chem 270: 15938-15941
        doi: 10.1074/jbc.270.27.15938

    104. Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM (2011) The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile. Proc Natl Acad Sci U S A 108: 15201-15206
        doi: 10.1073/pnas.1103746108

    105. Wang F, Alain T, Szretter KJ, Stephenson K, Pol JG, Atherton MJ, Hoang HD, Fonseca BD, Zakaria C, Chen L, Rangwala Z, Hesch A, Chan ESY, Tuinman C, Suthar MS, Jiang Z, Ashkar AA, Thomas G, Kozma SC, Gale M Jr, Fitzgerald KA, Diamond MS, Mossman K, Sonenberg N, Wan Y, Lichty BD (2016) S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3. Nat Immunol 17: 514-522
        doi: 10.1038/ni.3433

    106. Wang HC, Wu HC, Chen CF, Fausto N, Lei HY, Su IJ (2003) Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol 163: 2441-2449
        doi: 10.1016/S0002-9440(10)63599-7

    107. Wang HY, Yang SL, Liang HF, Li CH (2014) HBx protein promotes oval cell proliferation by up-regulation of cyclin D1 via activation of the MEK/ERK and PI3K/Akt pathways. Int J Mol Sci 15: 3507-3518
        doi: 10.3390/ijms15033507

    108. Wang J, Chen J, Liu Y, Zeng X, Wei M, Wu S, Xiong Q, Song F, Yuan X, Xiao Y, Cao Y, Li C, Chen L, Guo M, Shi YB, Sun G, Guo D (2019) Hepatitis B Virus Induces Autophagy to Promote its Replication by the Axis of miR-192-3p-XIAP Through NF kappa B Signaling. Hepatology 69: 974-992
        doi: 10.1002/hep.30248

    109. Wang M, Qiu N, Lu S, Xiu D, Yu J, Wang XT, Lu F, Li T, Liu X, Zhuang H (2013) Serum hepatitis B surface antigen is correlated with intrahepatic total HBV DNA and cccDNA in treatment-naive patients with chronic hepatitis B but not in patients with HBV related hepatocellular carcinoma. J Med Virol 85: 219-227
        doi: 10.1002/jmv.23461

    110. Wang P, Guo QS, Wang ZW, Qian HX (2013) HBx induces HepG-2 cells autophagy through PI3K/Akt-mTOR pathway. Mol Cell Biochem 372: 161-168
        doi: 10.1007/s11010-012-1457-x

    111. Wang X, Huo B, Liu J, Huang X, Zhang S, Feng T (2019) Hepatitis B virus X reduces hepatocyte apoptosis and promotes cell cycle progression through the Akt/mTOR pathway in vivo. Gene 691: 87-95
        doi: 10.1016/j.gene.2018.12.054

    112. Wang X, Lin Y, Kemper T, Chen J, Yuan Z, Liu S, Zhu Y, Broering R, Lu M (2020a) AMPK and Akt/mTOR signalling pathways participate in glucose-mediated regulation of hepatitis B virus replication and cellular autophagy. Cell Microbiol 22: e13131

    113. Wang X, Lin Y, Liu S, Zhu Y, Lu K, Broering R, Lu M (2020b) O-GlcNAcylation modulates HBV replication through regulating cellular autophagy at multiple levels. FASEB J 34: 14473-14489
        doi: 10.1096/fj.202001168RR

    114. Wang X, Wei Z, Lan T, He Y, Cheng B, Li R, Chen H, Li F, Liu G, Jiang B, Lin Y, Lu M, Meng Z (2021) CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation. Autophagy.
        doi: 10.1080/15548627.2021.1934271:1-18

    115. Weichhart T, Hengstschlager M, Linke M (2015) Regulation of innate immune cell function by mTOR. Nat Rev Immunol 15: 599-614
        doi: 10.1038/nri3901

    116. Weng L, Enomoto A, Miyoshi H, Takahashi K, Asai N, Morone N, Jiang P, An J, Kato T, Kuroda K, Watanabe T, Asai M, Ishida-Takagishi M, Murakumo Y, Nakashima H, Kaibuchi K, Takahashi M (2014) Regulation of cargo-selective endocytosis by dynamin 2 GTPase-activating protein girdin. EMBO J 33: 2098-2112
        doi: 10.15252/embj.201488289

    117. Wong VW, Wong GL, Chu WC, Chim AM, Ong A, Yeung DK, Yiu KK, Chu SH, Chan HY, Woo J, Chan FK, Chan HL (2012) Hepatitis B virus infection and fatty liver in the general population. J Hepatol 56: 533-540
        doi: 10.1016/j.jhep.2011.09.013

    118. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124: 471-484
        doi: 10.1016/j.cell.2006.01.016

    119. Xiang K, Wang B (2018) Role of the PI3K/AKT/mTOR pathway in hepatitis B virus infection and replication. Mol Med Rep 17: 4713-4719

    120. Xie N, Yuan K, Zhou L, Wang K, Chen HN, Lei Y, Lan J, Pu Q, Gao W, Zhang L, Shen G, Li Q, Xiao H, Tang H, Xiang R, He M, Feng P, Nice EC, Wei Y, Zhang H, Yang J, Huang C (2016) PRKAA/AMPK restricts HBV replication through promotion of autophagic degradation. Autophagy 12: 1507-1520
        doi: 10.1080/15548627.2016.1191857

    121. Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, Zhu Z, Jiao H, Lin J, Jiang K, Ding L, Zhang H, Cheng L, Fu H, Song Y, Jiang Y, Liu J, Wang R, Du N, Ye Q (2013) Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest 123: 630-645

    122. Yan H, Peng B, Liu Y, Xu G, He W, Ren B, Jing Z, Sui J, Li W (2014) Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide. J Virol 88: 3273-3284
        doi: 10.1128/JVI.03478-13

    123. Yang F, Yan S, He Y, Wang F, Song S, Guo Y, Zhou Q, Wang Y, Lin Z, Yang Y, Zhang W, Sun S (2008) Expression of hepatitis B virus proteins in transgenic mice alters lipid metabolism and induces oxidative stress in the liver. J Hepatol 48: 12-19
        doi: 10.1016/j.jhep.2007.06.021

    124. Yang JC, Teng CF, Wu HC, Tsai HW, Chuang HC, Tsai TF, Hsu YH, Huang W, Wu LW, Su IJ (2009) Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis. Hepatology 49: 1962-1971
        doi: 10.1002/hep.22889

    125. Yen CJ, Lin YJ, Yen CS, Tsai HW, Tsai TF, Chang KY, Huang WC, Lin PW, Chiang CW, Chang TT (2012) Hepatitis B virus X protein upregulates mTOR signaling through IKKbeta to increase cell proliferation and VEGF production in hepatocellular carcinoma. PLoS ONE 7: e41931
        doi: 10.1371/journal.pone.0041931

    126. Zhang X, Zhang E, Ma Z, Pei R, Jiang M, Schlaak JF, Roggendorf M, Lu M (2011) Modulation of hepatitis B virus replication and hepatocyte differentiation by MicroRNA-1. Hepatology 53: 1476-1485
        doi: 10.1002/hep.24195

    127. Zhou J, Tan SH, Nicolas V, Bauvy C, Yang ND, Zhang J, Xue Y, Codogno P, Shen HM (2013) Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion. Cell Res 23: 508-523
        doi: 10.1038/cr.2013.11

    128. Zhu M, Guo J, Li W, Xia H, Lu Y, Dong X, Chen Y, Xie X, Fu S, Li M (2015) HBx induced AFP receptor expressed to activate PI3K/AKT signal to promote expression of Src in liver cells and hepatoma cells. BMC Cancer 15: 362
        doi: 10.1186/s12885-015-1384-9

    129. Zhu M, Li W, Lu Y, Dong X, Lin B, Chen Y, Zhang X, Guo J, Li M (2017) HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway. Int J Cancer 140: 1346-1355
        doi: 10.1002/ijc.30553

  • 加载中


Article Metrics

Article views(3983) PDF downloads(12) Cited by()

Proportional views
    通讯作者: 陈斌,
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication

      Corresponding author: Zhongji Meng,
      Corresponding author: Mengji Lu,
    • 1. Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, China
    • 2. Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
    • 3. Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
    • 4. Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China


    Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that includes mTOR complex (mTORC) 1 and mTORC2. The mTOR pathway is activated in viral hepatitis, including hepatitis B virus (HBV) infection-induced hepatitis. Currently, chronic HBV infection remains one of the most serious public health issues worldwide. The unavailability of effective therapeutic strategies for HBV suggests that clarification of the pathogenesis of HBV infection is urgently required. Increasing evidence has shown that HBV infection can activate the mTOR pathway, indicating that HBV utilizes or hijacks the mTOR pathway to benefit its own replication. Therefore, the mTOR signaling pathway might be a crucial target for controlling HBV infection. Here, we summarize and discuss the latest findings from model biology research regarding the interaction between the mTOR signaling pathway and HBV replication.