YGLF motif in the Kaposi sarcoma herpes virus G-protein-coupled receptor adjusts NF-[kappa]B activation and paracrine actions

• Published in: Oncogene Vol. 33; no. 49; p. 5609
• Main Authors: Azzi, S, Smith, S S, Dwyer, J, Leclair, H M, Alexia, C, Hebda, J K, Dupin, N, Bidère, N, Gavard, J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 04.12.2014
• Subjects: Cancer; Herpes viruses; Immune system; Lymphocytes; Protein expression; Signal transduction
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.503

Kaposi sarcoma (KS) and primary effusion lymphoma (PEL) are two pathologies associated with KS herpes virus (KSHV/HHV-8) infection. KSHV genome contains several oncogenes, among which, the viral G-protein-coupled receptor (vGPCR open reading frame 74) has emerged as a major factor in KS pathogenicity. Indeed, vGPCR is a constitutively active receptor, whose expression is sufficient to drive cell transformation in vitro and tumour development in mice. However, neither the role of vGPCR in KSHV-infected B-lymphocytes nor the molecular basis for its constitutive activation is well understood. Here, we show that vGPCR expression contributes to nuclear factor-κB (NF-κB)-dependent cellular survival in both PEL cells and primary B cells from HIV-negative KS patients. We further identified within vGPCR an AP2 consensus binding motif, Y326GLF, that directs its localization between the plasma membrane and clathrin-coated vesicles. The introduction of a mutation in this site (Y326A) increased NF-κB activity and proinflammatory cytokines production. This correlated with exacerbated morphological rearrangement, migration and proliferation of non-infected monocytes. Collectively, our work raises the possibility that KSHV-infected B-lymphocytes use vGPCR to impact ultimately the immune response and communication within the tumour microenvironment in KSHV-associated pathologies.