KEGG   PATHWAY: ko05169Help
ko05169                     Pathway                                

Epstein-Barr virus infection
Epstein-Barr virus (EBV) is a gamma-herpes virus that widely infects human populations predominantly at an early age but remains mostly asymptomatic. EBV has been linked to a wide spectrum of human malignancies, including nasopharyngeal carcinoma and other hematologic cancers, like Hodgkin's lymphoma, Burkitt's lymphoma (BL), B-cell immunoblastic lymphoma in HIV patients, and posttransplant-associated lymphoproliferative diseases.  EBV has the unique ability to establish life-long latent infection in primary human B lymphocytes. During latent infection, EBV expresses a small subset of genes, including 6 nuclear antigens (EBNA-1, -2, -3A, -3B, -3C, and -LP), 3 latent membrane proteins (LMP-1, -2A, and -2B), 2 small noncoding RNAs (EBER-1 and 2). On the basis of these latent gene expression, three different latency patterns associated with the types of cancers are recognized.
Human Diseases; Infectious diseases: Viral
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Pathway map
ko05169  Epstein-Barr virus infection

Ortholog table
H00007  Hodgkin lymphoma
H00008  Burkitt lymphoma
H00054  Nasopharyngeal cancer
H00367  Infectious mononucleosis
K19450  envelope glycoprotein GP350
K04012  complement receptor type 2
K06465  B-lymphocyte antigen CD19
K19451  envelope glycoprotein H
K19452  envelope glycoprotein L
K19453  virion egress protein UL7
K06752  major histocompatibility complex, class II
K10159  toll-like receptor 2
K04729  myeloid differentiation primary response protein MyD88
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:]
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
K03156  tumor necrosis factor superfamily, member 2
K05405  interleukin 6
K22972  HHV4 large tegment protein deneddylase [EC:]
K12646  ATP-dependent RNA helicase DDX58 [EC:]
K12648  mitochondrial antiviral-signaling protein
K03174  TNF receptor-associated factor 3
K05410  TANK-binding kinase 1 [EC:]
K07211  inhibitor of nuclear factor kappa-B kinase subunit epsilon [EC:]
K09447  interferon regulatory factor 7
K19455  serine/threonine-protein kinase BGLF4 [EC:]
K05411  interferon regulatory factor 3
K05414  interferon alpha
K05415  interferon beta
K19460  latent membrane protein 2
K05130  interferon receptor 1
K05131  interferon receptor 2
K19459  latent membrane protein 1
K11217  Janus kinase 1 [EC:]
K11219  non-receptor tyrosine-protein kinase TYK2 [EC:]
K11220  signal transducer and activator of transcription 1
K11221  signal transducer and activator of transcription 2
K04693  interferon regulatory factor 9
K16195  eukaryotic translation initiation factor 2-alpha kinase 2 [EC:]
K14216  2'-5'-oligoadenylate synthetase [EC:]
K12671  C-X-C motif chemokine 10
K12159  ubiquitin cross-reactive protein
K04390  tumor necrosis factor receptor superfamily member 6
K02373  FAS-associated death domain protein
K04398  caspase 8 [EC:]
K04726  BH3 interacting domain death agonist
K19458  Epstein-Barr nuclear antigen 6
K16341  Bcl-2-like protein 11
K22973  HHV4 secreted protein BARF1
K02161  apoptosis regulator Bcl-2
K19463  apoptosis regulator BHRF1
K02159  apoptosis regulator BAX
K14021  Bcl-2 homologous antagonist/killer
K08738  cytochrome c
K02084  apoptotic protease-activating factor
K04399  caspase 9 [EC:]
K02187  caspase 3 [EC:]
K10784  T cell receptor alpha chain V region
K10785  T-cell receptor beta chain V region
K06451  T-cell surface glycoprotein CD3 epsilon chain
K06452  T-cell surface glycoprotein CD3 gamma chain
K06450  T-cell surface glycoprotein CD3 delta chain
K06453  CD3Z antigen, zeta polypeptide
K03061  26S proteasome regulatory subunit T1
K03062  26S proteasome regulatory subunit T2
K03063  26S proteasome regulatory subunit T3
K03064  26S proteasome regulatory subunit T4
K03065  26S proteasome regulatory subunit T5
K03066  26S proteasome regulatory subunit T6
K03028  26S proteasome regulatory subunit N1
K03032  26S proteasome regulatory subunit N2
K03033  26S proteasome regulatory subunit N3
K03035  26S proteasome regulatory subunit N5
K03036  26S proteasome regulatory subunit N6
K03037  26S proteasome regulatory subunit N7
K03038  26S proteasome regulatory subunit N8
K03039  26S proteasome regulatory subunit N9
K03029  26S proteasome regulatory subunit N10
K03030  26S proteasome regulatory subunit N11
K03031  26S proteasome regulatory subunit N12
K06691  26S proteasome regulatory subunit N13
K10881  26 proteasome complex subunit DSS1
K19461  Epstein-Barr nuclear antigen 1
K22974  HHV4 protein BNLF2a
K05653  ATP-binding cassette, subfamily B (MDR/TAP), member 2
K05654  ATP-binding cassette, subfamily B (MDR/TAP), member 3
K08058  TAP binding protein (tapasin)
K08056  protein disulfide-isomerase A3 [EC:]
K08057  calreticulin
K06751  major histocompatibility complex, class I
K08055  beta-2-microglobulin
K22975  HHV4 G-protein coupled receptor BILF1
K19456  Epstein-Barr nuclear antigen leader protein
K19457  Epstein-Barr nuclear antigen 2
K06063  SNW domain-containing protein 1
K11644  paired amphipathic helix protein Sin3a
K06067  histone deacetylase 1/2 [EC:]
K06065  nuclear receptor co-repressor 2
K19202  histone deacetylase complex subunit SAP30
K06066  CBF1 interacting corepressor
K21855  Epstein-Barr nuclear antigen 3
K21856  Epstein-Barr nuclear antigen 4
K06053  recombining binding protein suppressor of hairless
K06054  hairy and enhancer of split 1
K06468  low affinity immunoglobulin epsilon Fc receptor
K09279  runt-related transcription factor 3
K04377  Myc proto-oncogene protein
K11838  ubiquitin carboxyl-terminal hydrolase 7 [EC:]
K19462  trans-activator protein BZLF1
K06643  E3 ubiquitin-protein ligase Mdm2 [EC:]
K04451  tumor protein p53
K06625  cyclin-dependent kinase inhibitor 1A
K04402  growth arrest and DNA-damage-inducible protein
K10140  DNA damage-binding protein 2
K03511  DNA polymerase kappa [EC:]
K09849  TNF receptor-associated factor 5
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:]
K04466  mitogen-activated protein kinase kinase kinase 14 [EC:]
K09253  transcription factor RelB
K04469  nuclear factor of kappa light polypeptide gene enhancer in B-cells 2
K03171  tumor necrosis factor receptor type 1-associated DEATH domain protein
K02581  NF-kappa-B inhibitor beta
K05872  NF-kappa-B inhibitor epsilon
K04430  mitogen-activated protein kinase kinase 4 [EC:]
K04431  mitogen-activated protein kinase kinase 7 [EC:]
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:]
K03173  TNF receptor-associated factor 2 [EC:]
K02861  receptor-interacting serine/threonine-protein kinase 1 [EC:]
K04432  mitogen-activated protein kinase kinase 3 [EC:]
K04433  mitogen-activated protein kinase kinase 6 [EC:]
K04441  p38 MAP kinase [EC:]
K04448  transcription factor AP-1
K01510  apyrase [EC:]
K03160  tumor necrosis factor receptor superfamily member 5
K06256  CD44 antigen
K05718  integrin alpha L
K06492  CD58 antigen
K06490  intercellular adhesion molecule 1
K07606  vimentin
K11859  tumor necrosis factor, alpha-induced protein 3 [EC:]
K11218  Janus kinase 3 [EC:]
K04692  signal transducer and activator of transcription 3
K05854  tyrosine-protein kinase Lyn [EC:]
K05855  spleen tyrosine kinase [EC:]
K10591  E3 ubiquitin-protein ligase NEDD4 [EC:]
K04392  Ras-related C3 botulinum toxin substrate 1
K06856  immunoglobulin heavy chain
K07370  Bruton agammaglobulinemia tyrosine kinase [EC:]
K07371  B-cell linker protein
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:]
K03875  F-box and leucine-rich repeat protein 1 (S-phase kinase-associated protein 2)
K06624  cyclin-dependent kinase inhibitor 1B
K04503  G1/S-specific cyclin-D1
K10151  G1/S-specific cyclin-D2
K10152  G1/S-specific cyclin-D3
K02089  cyclin-dependent kinase 4 [EC:]
K02091  cyclin-dependent kinase 6 [EC:]
K06627  cyclin-A
K06626  G1/S-specific cyclin-E1
K02206  cyclin-dependent kinase 2 [EC:]
K06618  retinoblastoma-associated protein
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
C00076  Calcium cation
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Young LS, Rickinson AB.
Epstein-Barr virus: 40 years on.
Nat Rev Cancer 4:757-68 (2004)
Saha A, Robertson ES
Epstein-Barr virus-associated B-cell lymphomas: pathogenesis and clinical outcomes.
Clin Cancer Res 17:3056-63 (2011)
Ning S
Innate immune modulation in EBV infection.
Herpesviridae 2:1 (2011)
Stanfield BA, Luftig MA
Recent advances in understanding Epstein-Barr virus.
F1000Res 6:386 (2017)
van Gent M, Braem SG, de Jong A, Delagic N, Peeters JG, Boer IG, Moynagh PN, Kremmer E, Wiertz EJ, Ovaa H, Griffin BD, Ressing ME
Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling.
PLoS Pathog 10:e1003960 (2014)
Rajsbaum R, Garcia-Sastre A
Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways.
Trends Microbiol 21:421-9 (2013)
Hoffmann HH, Schneider WM, Rice CM
Interferons and viruses: an evolutionary arms race of molecular interactions.
Trends Immunol 36:124-38 (2015)
Spender LC, Inman GJ
Inhibition of germinal centre apoptotic programmes by epstein-barr virus.
Adv Hematol 2011:829525 (2011)
Fu Q, He C, Mao ZR
Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells.
J Zhejiang Univ Sci B 14:8-24 (2013)
Wang Y, Banerjee S, Ding L, Cai C, Wei F, Cai Q
The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers.
Virol Sin 32:357-368 (2017)
Melchjorsen J
Learning from the messengers: innate sensing of viruses and cytokine regulation of immunity - clues for treatments and vaccines.
Viruses 5:470-527 (2013)
Hansen TH, Bouvier M
MHC class I antigen presentation: learning from viral evasion strategies.
Nat Rev Immunol 9:503-13 (2009)
Ressing ME, Horst D, Griffin BD, Tellam J, Zuo J, Khanna R, Rowe M, Wiertz EJ
Epstein-Barr virus evasion of CD8(+) and CD4(+) T cell immunity via concerted actions of multiple gene products.
Semin Cancer Biol 18:397-408 (2008)
Horst D, Verweij MC, Davison AJ, Ressing ME, Wiertz EJ
Viral evasion of T cell immunity: ancient mechanisms offering new applications.
Curr Opin Immunol 23:96-103 (2011)
Ghosh Roy S, Robertson ES, Saha A
Epigenetic Impact on EBV Associated B-Cell Lymphomagenesis.
Biomolecules 6:E46 (2016)
Dawson CW, Port RJ, Young LS
The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC).
Semin Cancer Biol 22:144-53 (2012)
Cai Q, Chen K, Young KH
Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorders.
Exp Mol Med 47:e133 (2015)
Zheng H, Li LL, Hu DS, Deng XY, Cao Y
Role of Epstein-Barr virus encoded latent membrane protein 1 in the carcinogenesis of nasopharyngeal carcinoma.
Cell Mol Immunol 4:185-96 (2007)
Ersing I, Bernhardt K, Gewurz BE
NF-kappaB and IRF7 pathway activation by Epstein-Barr virus Latent Membrane Protein 1.
Viruses 5:1587-606 (2013)
Wang LW, Jiang S, Gewurz BE
Epstein-Barr Virus LMP1-Mediated Oncogenicity.
J Virol 91:e01718-16 (2017)
Mori N, Morishita M, Tsukazaki T, Yamamoto N
Repression of Smad-dependent transforming growth factor-beta signaling by Epstein-Barr virus latent membrane protein 1 through nuclear factor-kappaB.
Int J Cancer 105:661-8 (2003)
Edwards RH, Marquitz AR, Raab-Traub N
Changes in expression induced by Epstein-Barr Virus LMP1-CTAR1: potential role of bcl3.
MBio 6:e00441-15 (2015)
Thorley-Lawson DA
Epstein-Barr virus: exploiting the immune system.
Nat Rev Immunol 1:75-82 (2001)
Eliopoulos AG, Young LS
LMP1 structure and signal transduction.
Semin Cancer Biol 11:435-44 (2001)
Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L
Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP.
J Biol Chem 278:47753-61 (2003)
Kang H, Kiess A, Chung CH
Emerging biomarkers in head and neck cancer in the era of genomics.
Nat Rev Clin Oncol 12:11-26 (2015)
Tornesello ML, Annunziata C, Tornesello AL, Buonaguro L, Buonaguro FM
Human Oncoviruses and p53 Tumor Suppressor Pathway Deregulation at the Origin of Human Cancers.
Cancers (Basel) 10:E213 (2018)
Sato Y, Kamura T, Shirata N, Murata T, Kudoh A, Iwahori S, Nakayama S, Isomura H, Nishiyama Y, Tsurumi T
Degradation of phosphorylated p53 by viral protein-ECS E3 ligase complex.
PLoS Pathog 5:e1000530 (2009)
Saha A, Murakami M, Kumar P, Bajaj B, Sims K, Robertson ES
Epstein-Barr virus nuclear antigen 3C augments Mdm2-mediated p53 ubiquitination and degradation by deubiquitinating Mdm2.
J Virol 83:4652-69 (2009)
Yi F, Saha A, Murakami M, Kumar P, Knight JS, Cai Q, Choudhuri T, Robertson ES
Epstein-Barr virus nuclear antigen 3C targets p53 and modulates its transcriptional and apoptotic activities.
Virology 388:236-47 (2009)
Kumar P, Murakami M, Kaul R, Saha A, Cai Q, Robertson ES
Deregulation of the cell cycle machinery by Epstein-Barr virus nuclear antigen 3C.
Future Virol 4:79-91 (2009)
Longnecker R
Epstein-Barr virus latency: LMP2, a regulator or means for Epstein-Barr virus persistence?
Adv Cancer Res 79:175-200 (2000)
El-Sharkawy A, Al Zaidan L, Malki A
Epstein-Barr Virus-Associated Malignancies: Roles of Viral Oncoproteins in Carcinogenesis.
Front Oncol 8:265 (2018)
Dolcetti R, Masucci MG
Epstein-Barr virus: induction and control of cell transformation.
J Cell Physiol 196:207-18 (2003)
Saha A, Halder S, Upadhyay SK, Lu J, Kumar P, Murakami M, Cai Q, Robertson ES
Epstein-Barr virus nuclear antigen 3C facilitates G1-S transition by stabilizing and enhancing the function of cyclin D1.
PLoS Pathog 7:e1001275 (2011)
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