Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture.
Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8, a virus that appears to be involved in the pathogenesis of Kaposi's sarcoma and primary effusion lymphomas, encodes a G protein-coupled receptor (KSHV-GPCR) that exhibits constitutive signaling. In this report, we show that two chemokines, interleukin 8 (IL-8) and growth-related protein-alpha, activate KSHV-GPCR over constitutive levels. Moreover, as with human receptors, the integrity of the ELR motif of these chemokines is required for activation of KSHV-GPCR. Other residues that are required for IL-8 binding to human chemokine receptors CXCR1 and CXCR2 are important for KSHV-GPCR activation also. Thus, it appears that the ELR binding site and other key domains of ELR chemokine activation have been preserved in the virus KSHV-GPCR. The results suggest that KSHV-GPCR originated from CXCR1 or CXCR2 and that activation of KSHV-GPCR by endogenous chemokines may affect the pathobiology of KSHV infection in humans.
Gershengorn
M C
MC
Division of Molecular Medicine, Department of Medicine, Cornell University Medical College and The New York Hospital, New York 10021, USA. mcgersh@mail.med.cornell.edu
Geras-Raaka
E
E
Varma
A
A
Clark-Lewis
I
I
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D018925:Chemokines / Q000494:pharmacology*; D019743:Chemokines, CXC / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D019288:Herpesvirus 8, Human; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010978:Platelet Factor 4 / Q000494:pharmacology; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C115448:G protein-coupled receptor, Human herpesvirus 8; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D009842:Oligopeptides; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D010978:Platelet Factor 4; D019204:GTP-Binding Proteins