KEGG   PATHWAY: ko05161
ko05161                     Pathway                                
Hepatitis B
Hepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and converted into a covalently closed circular molecule cccDNA. The cccDNA is the template for transcription of all viral RNAs including the pregenomic RNA (pgRNA), encoding for 7 viral proteins: large, middle, and small envelope proteins (LHBs, MHBs, and SHBs) that form the surface antigen (HBsAg), the core antigen (HBcAg), the e antigen (HBeAg), the HBV polymerase, and the regulatory protein X (HBx). The pgRNA interacts with the viral polymerase protein to initiate the encapsidation into the core particles. Through endoplasmic reticulum, the core particles finish assembling with the envelope proteins and are released. HBV infection leads to a wide spectrum of liver diseases raging from chronic hepatitis, cirrhosis to hepatocellular carcinoma. The mechanism of liver injury is still not clear. However, HBV proteins target host proteins, involved in a variety of functions, thus regulating transcription, cellular signaling cascades, proliferation, differentiation, and apoptosis.
Human Diseases; Infectious disease: viral
Pathway map
ko05161  Hepatitis B

H00412  Hepatitis B
D00353  Lamivudine (JAN/USP/INN)
D01655  Adefovir dipivoxil (USAN)
D01982  Tenofovir disoproxil fumarate (JAN/USAN)
D02768  Adefovir (USAN/INN)
D03537  Clevudine (USAN)
D04008  Entecavir (USP)
D04757  Lobucavir (USAN/INN)
D05588  Pradefovir mesylate (USAN)
D06074  Tenofovir (USAN)
D06196  Torcitabine (USAN/INN)
D06259  Tuvirumab (USAN/INN)
D06278  Valtorcitabine dihydrochloride (USAN)
D06675  Telbivudine (USAN/INN)
D07896  Entecavir (INN)
D10428  Tenofovir alafenamide (USAN/INN)
D10605  Tenofovir alafenamide fumarate (JAN/USAN)
D10834  Tenofovir disoproxil phosphate
D10894  Valtorcitabine (INN)
D11391  Tenofovir disoproxil maleate
D12054  Vebicorvir (USAN/INN)
D12126  Bersacapavir (USAN/INN)
D12503  Linvencorvir (USAN/INN)
D12631  Tobevibart (USAN/INN)
K23128  Orthohepadnavirus large envelope protein
K06255  basement membrane-specific heparan sulfate proteoglycan core protein
K14341  solute carrier family 10 (sodium/bile acid cotransporter), member 1
K21854  Orthohepadnavirus protein X
K23129  Orthohepadnavirus capsid protein
K21037  Hepadnaviridae DNA polymerase / reverse transcriptase / ribonuclease H [EC:]
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K04674  TGF-beta receptor type-1 [EC:]
K04388  TGF-beta receptor type-2 [EC:]
K23605  mothers against decapentaplegic homolog 3
K06625  cyclin-dependent kinase inhibitor 1A
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:]
K04377  Myc proto-oncogene protein
K12496  early growth response protein 2
K12497  early growth response protein 3
K04498  E1A/CREB-binding protein [EC:]
K04389  tumor necrosis factor ligand superfamily member 6
K10610  DNA damage-binding protein 1
K10140  DNA damage-binding protein 2
K04416  mitogen-activated protein kinase kinase kinase 1 [EC:]
K16197  14-3-3 protein beta/theta/zeta
K04430  mitogen-activated protein kinase kinase 4 [EC:]
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K04734  NF-kappa-B inhibitor alpha
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K01403  matrix metalloproteinase-9 (gelatinase B) [EC:]
K02161  apoptosis regulator Bcl-2
K02158  Bcl-2-antagonist of cell death
K04390  tumor necrosis factor receptor superfamily member 6
K02373  FAS-associated death domain protein
K04398  caspase 8 [EC:]
K04400  caspase 10 [EC:]
K04726  BH3 interacting domain death agonist
K02159  apoptosis regulator BAX
K02084  apoptotic protease-activating factor
K08738  cytochrome c
K04399  caspase 9 [EC:]
K02187  caspase 3 [EC:]
K04741  caspase 12 [EC:3.4.22.-]
K08731  baculoviral IAP repeat-containing protein 5
K04451  tumor protein p53
K06627  cyclin-A
K02206  cyclin-dependent kinase 2 [EC:]
K06626  G1/S-specific cyclin-E1
K06618  retinoblastoma-associated protein
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
K03662  V-type H+-transporting ATPase S1 subunit
K02677  classical protein kinase C alpha type [EC:]
K19662  classical protein kinase C beta type [EC:]
K19663  classical protein kinase C gamma type [EC:]
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K17332  nuclear factor of activated T-cells, cytoplasmic 2
K17333  nuclear factor of activated T-cells, cytoplasmic 3
K17334  nuclear factor of activated T-cells, cytoplasmic 4
K03156  tumor necrosis factor superfamily, member 2
K11217  Janus kinase 1 [EC:]
K04447  Janus kinase 2 [EC:]
K11218  Janus kinase 3 [EC:]
K11219  non-receptor tyrosine-protein kinase TYK2 [EC:]
K04692  signal transducer and activator of transcription 3
K11220  signal transducer and activator of transcription 1
K11221  signal transducer and activator of transcription 2
K11222  signal transducer and activator of transcription 4
K11223  signal transducer and activator of transcription 5A
K11224  signal transducer and activator of transcription 5B
K11225  signal transducer and activator of transcription 6
K15041  voltage-dependent anion channel protein 3
K05871  focal adhesion kinase 2 [EC:]
K05704  tyrosine-protein kinase Src [EC:]
K04364  growth factor receptor-bound protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K04448  transcription factor AP-1
K04501  mothers against decapentaplegic homolog 4
K04450  cyclic AMP-dependent transcription factor ATF-2
K05870  cyclic AMP-responsive element-binding protein 1
K09048  cyclic AMP-responsive element-binding protein 3
K04374  cyclic AMP-dependent transcription factor ATF-4
K09047  cyclic AMP-responsive element-binding protein 5
K09049  cyclic AMP-dependent transcription factor ATF-6 beta
K10030  interleukin 8
K04802  proliferating cell nuclear antigen
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K04379  proto-oncogene protein c-fos
K04375  ETS domain-containing protein Elk-1
K10159  toll-like receptor 2
K04729  myeloid differentiation primary response protein MyD88
K05403  toll-interleukin 1 receptor (TIR) domain-containing adaptor protein
K10160  toll-like receptor 4
K04733  interleukin-1 receptor-associated kinase 4 [EC:]
K04730  interleukin-1 receptor-associated kinase 1 [EC:]
K03175  TNF receptor-associated factor 6 [EC:]
K04403  TAK1-binding protein 1
K04404  TAK1-binding protein 2
K04427  mitogen-activated protein kinase kinase kinase 7 [EC:]
K05405  interleukin 6
K04432  mitogen-activated protein kinase kinase 3 [EC:]
K04433  mitogen-activated protein kinase kinase 6 [EC:]
K04441  p38 MAP kinase [EC:]
K04431  mitogen-activated protein kinase kinase 7 [EC:]
K05409  TRIF-related adaptor molecule
K05401  toll-like receptor 3
K05842  toll-like receptor adapter molecule 1
K12646  ATP-dependent RNA helicase DDX58 [EC:]
K12647  interferon-induced helicase C domain-containing protein 1 [EC:]
K12648  mitochondrial antiviral-signaling protein
K03174  TNF receptor-associated factor 3
K07211  inhibitor of nuclear factor kappa-B kinase subunit epsilon [EC:]
K05410  TANK-binding kinase 1 [EC:]
K11594  ATP-dependent RNA helicase DDX3X [EC:]
K05411  interferon regulatory factor 3
K09447  interferon regulatory factor 7
K05414  interferon alpha
K05415  interferon beta
K05130  interferon receptor 1
C00076  Calcium cation
Caballero A, Tabernero D, Buti M, Rodriguez-Frias F
Hepatitis B virus: The challenge of an ancient virus with multiple faces and a remarkable replication strategy.
Antiviral Res 158:34-44 (2018)
Walsh R, Locarnini S
Hepatitis B precore protein: pathogenic potential and therapeutic promise.
Yonsei Med J 53:875-85 (2012)
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Present and future therapies of hepatitis B: From discovery to cure.
Hepatology 62:1893-908 (2015)
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Hepatol Res 46:871-7 (2016)
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Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B.
Hepatology 49:1203-17 (2009)
Yoo YG, Lee MO
Hepatitis B virus X protein induces expression of Fas ligand gene through enhancing transcriptional activity of early growth response factor.
J Biol Chem 279:36242-9 (2004)
Zhang X, Zhang H, Ye L
Effects of hepatitis B virus X protein on the development of liver cancer.
J Lab Clin Med 147:58-66 (2006)
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Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis.
Adv Cancer Res 103:75-109 (2009)
Benhenda S, Cougot D, Neuveut C, Buendia MA
Liver cell transformation in chronic HBV infection.
Viruses 1:630-46 (2009)
Diao J, Khine AA, Sarangi F, Hsu E, Iorio C, Tibbles LA, Woodgett JR, Penninger J, Richardson CD
X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway.
J Biol Chem 276:8328-40 (2001)
Park NH, Song IH, Chung YH
Chronic hepatitis B in hepatocarcinogenesis.
Postgrad Med J 82:507-15 (2006)
Lin S, Zhang YJ
Interference of Apoptosis by Hepatitis B Virus.
Viruses 9:E230 (2017)
Zhang X, Dong N, Yin L, Cai N, Ma H, You J, Zhang H, Wang H, He R, Ye L
Hepatitis B virus X protein upregulates survivin expression in hepatoma tissues.
J Med Virol 77:374-81 (2005)
Kim HJ, Kim SY, Kim J, Lee H, Choi M, Kim JK, Ahn JK
Hepatitis B virus X protein induces apoptosis by enhancing translocation of Bax to mitochondria.
IUBMB Life 60:473-80 (2008)
Ng SA, Lee C
Hepatitis B virus X gene and hepatocarcinogenesis.
J Gastroenterol 46:974-90 (2011)
Cong YS, Yao YL, Yang WM, Kuzhandaivelu N, Seto E
The hepatitis B virus X-associated protein, XAP3, is a protein kinase C-binding protein.
J Biol Chem 272:16482-9 (1997)
Panteva M, Korkaya H, Jameel S
Hepatitis viruses and the MAPK pathway: is this a survival strategy?
Virus Res 92:131-40 (2003)
Lee YH, Yun Y
HBx protein of hepatitis B virus activates Jak1-STAT signaling.
J Biol Chem 273:25510-5 (1998)
Tan A, Yeh SH, Liu CJ, Cheung C, Chen PJ
Viral hepatocarcinogenesis: from infection to cancer.
Liver Int 28:175-88 (2008)
Chami M, Oules B, Paterlini-Brechot P
Cytobiological consequences of calcium-signaling alterations induced by human viral proteins.
Biochim Biophys Acta 1763:1344-62 (2006)
Ganem D
Virology. The X files--one step closer to closure.
Science 294:2299-300 (2001)
Chung TW, Lee YC, Kim CH
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 18:1123-5 (2004)
Gurtsevitch VE
Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis.
Biochemistry (Mosc) 73:504-13 (2008)
Schadler S, Hildt E
HBV life cycle: entry and morphogenesis.
Viruses 1:185-209 (2009)
Ortega-Prieto AM, Dorner M
Immune Evasion Strategies during Chronic Hepatitis B and C Virus Infection.
Vaccines (Basel) 5:E24 (2017)
Nosratabadi R, Alavian SM, Zare-Bidaki M, Shahrokhi VM, Arababadi MK
Innate immunity related pathogen recognition receptors and chronic hepatitis B infection.
Mol Immunol 90:64-73 (2017)
Bagheri V, Askari A, Arababadi MK, Kennedy D
Can Toll-Like Receptor (TLR) 2 be considered as a new target for immunotherapy against hepatitis B infection?
Hum Immunol 75:549-54 (2014)
Zhang E, Lu M
Toll-like receptor (TLR)-mediated innate immune responses in the control of hepatitis B virus (HBV) infection.
Med Microbiol Immunol 204:11-20 (2015)
Yu S, Chen J, Wu M, Chen H, Kato N, Yuan Z
Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3.
J Gen Virol 91:2080-90 (2010)
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New insights into how HBV manipulates the innate immune response to establish acute and persistent infection.
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ko04010  MAPK signaling pathway
ko04064  NF-kappa B signaling pathway
ko04110  Cell cycle
ko04115  p53 signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04210  Apoptosis
ko04620  Toll-like receptor signaling pathway
ko04622  RIG-I-like receptor signaling pathway
ko04630  JAK-STAT signaling pathway

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