Functional analysis of Kaposi's sarcoma-associated herpesvirus vFLIP expression reveals a new mode of IRES-mediated translation

Zulkefley Othman, Mariam K. Sulaiman, Margaret M. Willcocks, Nathalie Ulryck, David J. Blackbourn, Bruno Sargueil, Lisa O. Roberts, Nicolas Locker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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 NF?B 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.

Original languageEnglish
Pages (from-to)1803-1814
Number of pages12
JournalRNA
Volume20
Issue number11
DOIs
Publication statusPublished - 1 Nov 2014

Keywords

  • EIF4E
  • IRES
  • RNA structure
  • Translation
  • Viruses

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