Chemokine-directed trafficking of receptor stimulus to different g proteins: selective inducible and constitutive signaling by human herpesvirus 6-encoded chemokine receptor U51.
The human herpes virus 6 (HHV-6)-encoded chemokine receptor U51 constitutively activates phospholipase C (PLC) and inhibits cAMP-responsive element (CRE)-mediated gene transcription via the activation of G(q/11) proteins. Yet, chemokines known to bind U51 differentially regulate U51 coupling to G proteins. CCL5/RANTES induced pertussis toxin (PTX)-insensitive increases in PLC activity and changes in intracellular free calcium concentration ([Ca2+]i), whereas both CCL2/MCP-1 and CCL11/eotaxin failed to stimulate PLC activity or increase [Ca2+]i. In contrast, all three chemokines counteracted the effects of U51 on CRE activity via the activation of PTX-sensitive G(i/o) proteins. For each of the tested chemokines, coexpression of U51 with a variety of G alpha subunits, however, revealed a distinct profile for preferred G-protein coupling, which could be shifted by modulation of the relative expression of G proteins. These findings are consistent with a chemokine-selective trafficking of receptor stimulus to distinct G proteins and suggest that the constitutive activity of U51 and the chemokine-induced signaling involve different active states of the receptor. By virtue of its ability to constitutively activate signaling pathways, its G-protein promiscuity, and the chemokine-directed trafficking of receptor stimulus, U51 can be considered a sensitive and versatile virally encoded signaling device, potentially of importance in HHV-6-related pathologies.
Fitzsimons
Carlos P
CP
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, The Netherlands.
Gompels
Ursula A
UA
Verzijl
Dennis
D
Vischer
Henry F
HF
Mattick
Claire
C
Leurs
Rob
R
Smit
Martine J
MJ
D000818:Animals; D019556:COS Cells; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000494:pharmacology; D018946:Chemokine CCL5; D018925:Chemokines / Q000494:pharmacology*; D019742:Chemokines, CC / Q000494:pharmacology; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015654:Herpesvirus 6, Human / Q000472:pathogenicity; D006801:Humans; D008024:Ligands; D019707:Receptors, Chemokine / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D014162:Transfection
C515456:CCL11 protein, human; C483024:CCL5 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D044385:GTP-Binding Protein alpha Subunits; D008024:Ligands; D019707:Receptors, Chemokine; D011991:Receptors, Virus; C405384:U51 protein, human herpesvirus 6; D000242:Cyclic AMP