Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.
A G protein-coupled receptor (GPCR) is encoded within the genome of Kaposi's sarcoma- associated herpesvirus (KSHV)/human herpesvirus 8, a virus that may be involved in the pathogenesis of Kaposi's sarcoma and primary effusion lymphomas. KSHV-GPCR exhibits constitutive signaling activity that causes oncogenic transformation. We report that human interferon (IFN)-gamma-inducible protein 10 (HuIP-10), a C-X-C chemokine, specifically inhibits signaling of KSHV-GPCR. In contrast, monokine induced by IFN-gamma (HuMig), which like HuIP-10 is an agonist of C-X-C chemokine receptor 3, does not inhibit KSHV-GPCR signaling. Moreover, HuIP-10, but not HuMig, inhibits KSHV-GPCR-induced proliferation of NIH 3T3 cells. These results show that HuIP-10 is an inverse agonist that converts KSHV-GPCR from an active to an inactive state. Thus, a human chemokine inhibits constitutive signaling and cellular proliferation that is mediated by a receptor encoded by a human disease-associated herpesvirus.
Division of Molecular Medicine, Department of Medicine, Cornell University Medical College and The New York Hospital, New York 10021, USA.
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Geras-Raaka
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Varma
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Clark-Lewis
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Gershengorn
D016475:3T3 Cells; D000818:Animals; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000494:pharmacology* / Q000502:physiology; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D019707:Receptors, Chemokine / Q000502:physiology*; D011991:Receptors, Virus / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D019707:Receptors, Chemokine; D011991:Receptors, Virus