title: Functional analysis of Kaposi's sarcoma-associated herpesvirus vFLIP expression reveals a new mode of IRES-mediated translation.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus, the etiological agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). One of the key viral proteins that contributes to tumorigenesis is vFLIP, a viral homolog of the FLICE inhibitory protein. This KSHV protein interacts with the NFκB pathway to trigger the expression of antiapoptotic and proinflammatory genes and ultimately leads to tumor formation. The expression of vFLIP is regulated at the translational level by an internal ribosomal entry site (IRES) element. However, the precise mechanism by which ribosomes are recruited internally and the exact location of the IRES has remained elusive. Here we show that a 252-nt fragment directly upstream of vFLIP, within a coding region, directs translation. We have established its RNA structure and demonstrate that IRES activity requires the presence of eIF4A and an intact eIF4G. Furthermore, and unusually for an IRES, eIF4E is part of the complex assembled onto the vFLIP IRES to direct translation. These molecular interactions define a new paradigm for IRES-mediated translation.
authors.affiliation: Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU27HE, United Kingdom.
authors.forename: Zulkefley
authors.initials: Z
authors.lastname: Othman
authors.affiliation: Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU27HE, United Kingdom.
authors.forename: Mariam K
authors.initials: MK
authors.lastname: Sulaiman
authors.affiliation: Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU27HE, United Kingdom.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Willcocks
authors.affiliation: Faculté des Sciences Pharmaceutiques et Biologiques, UMR8015, Université Paris Descartes, 75270 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ulryck
authors.affiliation: Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU27HE, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Blackbourn
authors.affiliation: Faculté des Sciences Pharmaceutiques et Biologiques, UMR8015, Université Paris Descartes, 75270 Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sargueil
authors.affiliation: Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU27HE, United Kingdom.
authors.forename: Lisa O
authors.initials: LO
authors.lastname: Roberts
authors.affiliation: Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU27HE, United Kingdom n.locker@surrey.ac.uk.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Locker
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics; D012270:Ribosomes / Q000378:metabolism; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D012367:RNA, Viral; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8
keywords: IRES; RNA structure; eIF4E; translation; viruses