title: YGLF motif in the Kaposi sarcoma herpes virus G-protein-coupled receptor adjusts NF-κB 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-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.
authors.affiliation: 1] CNRS, UMR8104, Paris, France [2] INSERM, U1016, Paris, France [3] Universite Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Azzi
authors.affiliation: 1] CNRS, UMR8104, Paris, France [2] INSERM, U1016, Paris, France [3] Universite Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: S S
authors.initials: SS
authors.lastname: Smith
authors.affiliation: 1] CNRS, UMR8104, Paris, France [2] INSERM, U1016, Paris, France [3] Universite Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Dwyer
authors.affiliation: 1] CNRS, UMR8104, Paris, France [2] INSERM, U1016, Paris, France [3] Universite Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: H M
authors.initials: HM
authors.lastname: Leclair
authors.affiliation: 1] INSERM, U1014, Hopital Paul Brousse, Villejuif, France [2] Universite Paris-Sud P11, Orsay, France [3] Equipe Labellisee Ligue contre le Cancer, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Alexia
authors.affiliation: 1] CNRS, UMR8104, Paris, France [2] INSERM, U1016, Paris, France [3] Universite Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: J K
authors.initials: JK
authors.lastname: Hebda
authors.affiliation: 1] Universite Paris Descartes, Sorbonne Paris Cite, Paris, France [2] Service de dermatologie, Hopital Cochin-Tarnier, AP-HP, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Dupin
authors.affiliation: 1] INSERM, U1014, Hopital Paul Brousse, Villejuif, France [2] Universite Paris-Sud P11, Orsay, France [3] Equipe Labellisee Ligue contre le Cancer, Villejuif, France.
authors.forename: N
authors.initials: N
authors.lastname: Bidère
authors.affiliation: 1] CNRS, UMR8104, Paris, France [2] INSERM, U1016, Paris, France [3] Universite Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Gavard
mesh_terms: D020816:Amino Acid Motifs; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D002465:Cell Movement; D002966:Clathrin / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D015658:HIV Infections; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D016366:Open Reading Frames; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000821:virology*; D015398:Signal Transduction
chemical_list: D002966:Clathrin; D016207:Cytokines; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled