YGLF motif in the Kaposi sarcoma herpes virus G-protein- coupled receptor adjusts NF-kB activation and paracrine actions

Abstract : 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-kB (NF-kB)-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, Y 326 GLF, that directs its localization between the plasma membrane and clathrin-coated vesicles. The introduction of a mutation in this site (Y 326 A) increased NF-kB 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.
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S Azzi, Ss Smith, J Dwyer, Hm Leclair, C Alexia, et al.. YGLF motif in the Kaposi sarcoma herpes virus G-protein- coupled receptor adjusts NF-kB activation and paracrine actions. Oncogene, Nature Publishing Group, 2013, pp.24292677. ⟨10.1038/onc.2013.503⟩. ⟨inserm-01078184⟩

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