Entry
Name
Human cytomegalovirus infection - Homo sapiens (human)
Description
Human cytomegalovirus (HCMV) is an enveloped, double-stranded DNA virus that is a member of beta-herpesvirus family. HCMV is best known for causing significant morbidity and mortality in immunocompromised populations. As with other herpesviruses, HCMV gB and gH/gL envelope glycoproteins are essential for virus entry. HCMV gB could activate the PDGFRA, and induce activation of the oncogenic PI3-K/AKT pathway. Though it is unlikely that HCMV by itself can act as an oncogenic factor, HCMV may have an oncomodulatory role, to catalyze an oncogenic process that has already been initiated. US28, one of the four HCMV-encoded vGPCRs (US27, US28, UL33 and UL78), also has a specific role in the oncomodulatory properties. In addition, HCMV has developed numerous mechanisms for manipulating the host immune system. The virally encoded US2, US3, US6 and US11 gene products all interfere with major histocompatibility complex (MHC) class I antigen presentation. HCMV encodes several immediate early (IE) antiapoptotic proteins (IE1, IE2, vMIA and vICA). These proteins might avoid immune clearance of infected tumor cells by cytotoxic lymphocytes and NK cells.
Class
Human Diseases; Infectious disease: viral
BRITE hierarchy
Pathway map
hsa05163 Human cytomegalovirus infection
Network
Element
N00385 HCMV gB to PDGFR-PI3K signaling pathway
N00386 HCMV gB to PDGFR-RAS-ERK signaling pathway
N00387 HCMV IE1-72/IE2-86 to PI3K signaling pathway
N00388 HCMV UL38 to MTOR signaling pathway
N00389 HCMV IE1-72 to transcription
N00391 HCMV gB to EGFR-PI3K-NFKB signaling pathway
N00392 HCMV gB to EGFR-RAS-ERK signaling pathway
N00394 HCMV gH to ITGA/B-RhoA signaling pathway
N00396 HCMV UL82 to cGAS-STING signaling pathway
N00397 HCMV UL26 to NFKB signaling pathway
N00398 HCMV IE2-86 to TNF-NFKB signaling pathway
N00400 HCMV US28 to GNB/G-PI3K-NFKB signaling pathway
N00402 HCMV US28 to GNAQ-PLCB/G-calcineurin signaling pathway
N00404 HCMV US28 to GNAI-AC-PKA signaling pathway
N00406 HCMV US28 to GNA12/13-Rho signaling pathway
N00407 HCMV UL33 to GNAQ-PLCB/G-calcineurin signaling pathway
N00409 HCMV UL33 to GNB/G-Rho signaling pathway
N00411 HCMV UL33 to GNAS-AC-PKA signaling pathway
N00412 HCMV UL33 to GNAI-AC-PKA signaling pathway
N00414 HCMV US27 to CXCR4-GNB/G-PLCB-PKC signaling pathway
N00416 HCMV vIL10 to IL10-JAK-STAT signaling pathway
N00417 HCMV US6 to antigen processing and presentation by MHC class I molecules
N00418 HCMV US2/11 to antigen processing and presentation by MHC class I molecules
N00419 HCMV US3/10 to antigen processing and presentation by MHC class I molecules
N00420 HCMV IE2-86 to p21-cell cycle G1/S
N00421 HCMV IE2-86 to p21-cell cycle G1/S
N00422 HCMV IE2-86 to cell cycle G1/S
N00423 HCMV IE1-72 to cell cycle G1/S
N00424 HCMV pp71 to cell cycle G1/S
N00425 HCMV UL36 to crosstalk between extrinsic and intrinsic apoptotic pathways
N00426 HCMV UL37x1 to crosstalk between extrinsic and intrinsic apoptotic pathways
N00427 HCMV vCXCL to CXCR-GNB/G-PI3K-AKT signaling pathway
N00429 HCMV UL22A to CCR5-GNB/G-PLCB/G-PKC signaling pathway
Disease
H00368 Cytomegalovirus infection; CMV infection
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625 ]
1029 CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621 ]
10488 CREB3; cAMP responsive element binding protein 3 [KO:K09048 ]
11214 AKAP13; A-kinase anchoring protein 13 [KO:K16529 ]
1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467 ] [EC:2.7.11.10 ]
1230 CCR1; C-C motif chemokine receptor 1 [KO:K04176 ]
1232 CCR3; C-C motif chemokine receptor 3 [KO:K04178 ]
1234 CCR5; C-C motif chemokine receptor 5 [KO:K04180 ]
1385 CREB1; cAMP responsive element binding protein 1 [KO:K05870 ]
1386 ATF2; activating transcription factor 2 [KO:K04450 ]
1388 ATF6B; activating transcription factor 6 beta [KO:K09049 ]
1398 CRK; CRK proto-oncogene, adaptor protein [KO:K04438 ]
1399 CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438 ]
148327 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048 ]
1978 EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205 ]
2002 ELK1; ETS transcription factor ELK1 [KO:K04375 ]
23365 ARHGEF12; Rho guanine nucleotide exchange factor 12 [KO:K07532 ]
2767 GNA11; G protein subunit alpha 11 [KO:K04635 ]
2768 GNA12; G protein subunit alpha 12 [KO:K04346 ]
2770 GNAI1; G protein subunit alpha i1 [KO:K04630 ]
2771 GNAI2; G protein subunit alpha i2 [KO:K04630 ]
2773 GNAI3; G protein subunit alpha i3 [KO:K04630 ]
2775 GNAO1; G protein subunit alpha o1 [KO:K04534 ]
2790 GNG10; G protein subunit gamma 10 [KO:K04545 ]
2791 GNG11; G protein subunit gamma 11 [KO:K04546 ]
2792 GNGT1; G protein subunit gamma transducin 1 [KO:K04548 ]
2793 GNGT2; G protein subunit gamma transducin 2 [KO:K04549 ]
2885 GRB2; growth factor receptor bound protein 2 [KO:K04364 ]
3105 HLA-A; major histocompatibility complex, class I, A [KO:K06751 ]
3106 HLA-B; major histocompatibility complex, class I, B [KO:K06751 ]
3107 HLA-C; major histocompatibility complex, class I, C [KO:K06751 ]
3133 HLA-E; major histocompatibility complex, class I, E [KO:K06751 ]
3134 HLA-F; major histocompatibility complex, class I, F [KO:K06751 ]
3135 HLA-G; major histocompatibility complex, class I, G [KO:K06751 ]
3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833 ]
340061 STING1; stimulator of interferon response cGAMP interactor 1 [KO:K12654 ]
355 FAS; Fas cell surface death receptor [KO:K04390 ]
3554 IL1R1; interleukin 1 receptor type 1 [KO:K04386 ]
3576 CXCL8; C-X-C motif chemokine ligand 8 [KO:K10030 ]
3579 CXCR2; C-X-C motif chemokine receptor 2 [KO:K05050 ]
3587 IL10RA; interleukin 10 receptor subunit alpha [KO:K05134 ]
3588 IL10RB; interleukin 10 receptor subunit beta [KO:K05135 ]
3661 IRF3; interferon regulatory factor 3 [KO:K05411 ]
3708 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
3709 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959 ]
3710 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827 ]
387 RHOA; ras homolog family member A [KO:K04513 ]
388372 CCL4L1; C-C motif chemokine ligand 4 like 1 [KO:K12964 ]
414062 CCL3L3; C-C motif chemokine ligand 3 like 3 [KO:K05408 ]
4609 MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377 ]
468 ATF4; activating transcription factor 4 [KO:K04374 ]
4772 NFATC1; nuclear factor of activated T cells 1 [KO:K04446 ]
4773 NFATC2; nuclear factor of activated T cells 2 [KO:K17332 ]
4775 NFATC3; nuclear factor of activated T cells 3 [KO:K17333 ]
4776 NFATC4; nuclear factor of activated T cells 4 [KO:K17334 ]
4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580 ]
4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
5534 PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268 ]
5535 PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268 ]
5731 PTGER1; prostaglandin E receptor 1 [KO:K04258 ]
5732 PTGER2; prostaglandin E receptor 2 [KO:K04259 ]
5733 PTGER3; prostaglandin E receptor 3 [KO:K04260 ]
5734 PTGER4; prostaglandin E receptor 4 [KO:K04261 ]
578 BAK1; BCL2 antagonist/killer 1 [KO:K14021 ]
581 BAX; BCL2 associated X, apoptosis regulator [KO:K02159 ]
5925 RB1; RB transcriptional corepressor 1 [KO:K06618 ]
5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735 ]
6009 RHEB; Ras homolog, mTORC1 binding [KO:K07208 ]
6347 CCL2; C-C motif chemokine ligand 2 [KO:K14624 ]
6348 CCL3; C-C motif chemokine ligand 3 [KO:K05408 ]
6349 CCL3L1; C-C motif chemokine ligand 3 like 1 [KO:K05408 ]
6351 CCL4; C-C motif chemokine ligand 4 [KO:K12964 ]
6352 CCL5; C-C motif chemokine ligand 5 [KO:K12499 ]
637 BID; BH3 interacting domain death agonist [KO:K04726 ]
6376 CX3CL1; C-X3-C motif chemokine ligand 1 [KO:K05508 ]
6387 CXCL12; C-X-C motif chemokine ligand 12 [KO:K10031 ]
64764 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048 ]
6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099 ]
6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099 ]
6774 STAT3; signal transducer and activator of transcription 3 [KO:K04692 ]
6890 TAP1; transporter 1, ATP binding cassette subfamily B member [KO:K05653 ] [EC:7.4.2.14 ]
6891 TAP2; transporter 2, ATP binding cassette subfamily B member [KO:K05654 ] [EC:7.4.2.14 ]
7132 TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158 ]
7188 TRAF5; TNF receptor associated factor 5 [KO:K09849 ]
7422 VEGFA; vascular endothelial growth factor A [KO:K05448 ]
7852 CXCR4; C-X-C motif chemokine receptor 4 [KO:K04189 ]
84699 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210 ]
8717 TRADD; TNFRSF1A associated via death domain [KO:K03171 ]
8772 FADD; Fas associated via death domain [KO:K02373 ]
90993 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048 ]
9138 ARHGEF1; Rho guanine nucleotide exchange factor 1 [KO:K12330 ]
9560 CCL4L2; C-C motif chemokine ligand 4 like 2 [KO:K12964 ]
9564 BCAR1; BCAR1 scaffold protein, Cas family member [KO:K05726 ]
9586 CREB5; cAMP responsive element binding protein 5 [KO:K09047 ]
9826 ARHGEF11; Rho guanine nucleotide exchange factor 11 [KO:K12331 ]
Compound
C01245 D-myo-Inositol 1,4,5-trisphosphate
C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference
Authors
Michaelis M, Doerr HW, Cinatl J
Title
The story of human cytomegalovirus and cancer: increasing evidence and open questions.
Journal
Reference
Authors
Roy S, Arav-Boger R
Title
New cell-signaling pathways for controlling cytomegalovirus replication.
Journal
Reference
Authors
Cinatl J, Scholz M, Kotchetkov R, Vogel JU, Doerr HW
Title
Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology.
Journal
Reference
Authors
Evers DL, Wang X, Huang ES
Title
Cellular stress and signal transduction responses to human cytomegalovirus infection.
Journal
Reference
Authors
Murray MJ, Peters NE, Reeves MB
Title
Navigating the Host Cell Response during Entry into Sites of Latent Cytomegalovirus Infection.
Journal
Reference
Authors
Campadelli-Fiume G, Collins-McMillen D, Gianni T, Yurochko AD
Title
Integrins as Herpesvirus Receptors and Mediators of the Host Signalosome.
Journal
Reference
Authors
Fu YZ, Su S, Gao YQ, Wang PP, Huang ZF, Hu MM, Luo WW, Li S, Luo MH, Wang YY, Shu HB
Title
Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity.
Journal
Reference
Authors
Hancock MH, Nelson JA
Title
Modulation of the NFkappab Signalling Pathway by Human Cytomegalovirus.
Journal
Virology (Hyderabad) 1:104 (2017)
Reference
Authors
Rahman MM, McFadden G
Title
Modulation of NF-kappaB signalling by microbial pathogens.
Journal
Reference
Authors
Zhang J, Feng H, Xu S, Feng P
Title
Hijacking GPCRs by viral pathogens and tumor.
Journal
Reference
Authors
Lee S, Chung YH, Lee C
Title
US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection.
Journal
Reference
Authors
Langemeijer EV, Slinger E, de Munnik S, Schreiber A, Maussang D, Vischer H, Verkaar F, Leurs R, Siderius M, Smit MJ
Title
Constitutive beta-catenin signaling by the viral chemokine receptor US28.
Journal
Reference
Authors
Couty JP, Gershengorn MC
Title
G-protein-coupled receptors encoded by human herpesviruses.
Journal
Reference
Authors
Fiallos E, Judkins J, Matlaf L, Prichard M, Dittmer D, Cobbs C, Soroceanu L
Title
Human cytomegalovirus gene expression in long-term infected glioma stem cells.
Journal
Reference
Authors
Vischer HF, Siderius M, Leurs R, Smit MJ
Title
Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases?
Journal
Reference
Authors
Slinger E, Langemeijer E, Siderius M, Vischer HF, Smit MJ
Title
Herpesvirus-encoded GPCRs rewire cellular signaling.
Journal
Reference
Authors
Murphy PM
Title
Viral exploitation and subversion of the immune system through chemokine mimicry.
Journal
Reference
Authors
Vischer HF, Leurs R, Smit MJ
Title
HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks.
Journal
Reference
Authors
de Munnik SM, Smit MJ, Leurs R, Vischer HF
Title
Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors.
Journal
Reference
Authors
Michelson S
Title
Consequences of human cytomegalovirus mimicry.
Journal
Reference
Authors
Tu CC, Arnolds KL, O'Connor CM, Spencer JV
Title
Human Cytomegalovirus UL111A and US27 Gene Products Enhance the CXCL12/CXCR4 Signaling Axis via Distinct Mechanisms.
Journal
Reference
Authors
Busillo JM, Benovic JL
Title
Regulation of CXCR4 signaling.
Journal
Reference
Authors
Noriega V, Redmann V, Gardner T, Tortorella D
Title
Diverse immune evasion strategies by human cytomegalovirus.
Journal
Reference
Authors
Loureiro J, Ploegh HL
Title
Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions.
Journal
Reference
Authors
Fortunato EA, McElroy AK, Sanchez I, Spector DH
Title
Exploitation of cellular signaling and regulatory pathways by human cytomegalovirus.
Journal
Reference
Authors
Cinatl J Jr, Scholz M, Doerr HW
Title
Role of tumor cell immune escape mechanisms in cytomegalovirus-mediated oncomodulation.
Journal
Reference
Authors
Cinatl J Jr, Vogel JU, Kotchetkov R, Wilhelm Doerr H
Title
Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression.
Journal
Reference
Authors
Castillo JP, Kowalik TF
Title
Human cytomegalovirus immediate early proteins and cell growth control.
Journal
Reference
Authors
Kalejta RF
Title
Human cytomegalovirus pp71: a new viral tool to probe the mechanisms of cell cycle progression and oncogenesis controlled by the retinoblastoma family of tumor suppressors.
Journal
Reference
Authors
Brune W
Title
Inhibition of programmed cell death by cytomegaloviruses.
Journal
Reference
Authors
Brune W, Andoniou CE
Title
Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus.
Journal
Reference
Authors
Yamin R, Lecker LSM, Weisblum Y, Vitenshtein A, Le-Trilling VTK, Wolf DG, Mandelboim O
Title
HCMV vCXCL1 Binds Several Chemokine Receptors and Preferentially Attracts Neutrophils over NK Cells by Interacting with CXCR2.
Journal
Reference
Authors
Wang X, Sanchez J, Stone MJ, Payne RJ
Title
Sulfation of the Human Cytomegalovirus Protein UL22A Enhances Binding to the Chemokine RANTES.
Journal
Related pathway
hsa04612 Antigen processing and presentation
hsa04810 Regulation of actin cytoskeleton
KO pathway