Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74.
The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding protein (CREB) and that both pathways are modulated by their respective endogenous receptor ligands. By addition of specific pathway modulators against the G protein subunit Galphai, phospholipase C, protein kinase C, calcineurin, p38 MAP kinase, and MEK1, we find that the constitutive and ligand-dependent inductions are mediated by multiple yet similar pathways in both receptors. The NFAT and CREB transcription factors and their upstream activators are known inducers of host and virally encoded genes. We propose that the activity of these virally encoded chemokine receptors coordinates host and potentially viral gene expression similarly. As ORF74 is a known inducer of neoplasia, these findings may have important implications for cytomegalovirus-associated pathogenicity.
McLean
Katherine A
KA
Laboratory for Molecular Pharmacology, Department of Pharmacology, The Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
Holst
Peter J
PJ
Martini
Lene
L
Schwartz
Thue W
TW
Rosenkilde
Mette M
MM
D000818:Animals; D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D018925:Chemokines / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019707:Receptors, Chemokine / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000235:genetics* / Q000502:physiology*
D018925:Chemokines; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C105181:ORF74 protein, Human herpesvirus 8; D019707:Receptors, Chemokine; D014157:Transcription Factors; C411191:US28 receptor, Cytomegalovirus; D014764:Viral Proteins