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Interactions of picornavirus IRES elements with the cellular protein synthesis machinery

Reference	BBS/E/I/00000779
Principal Investigator / Supervisor	Professor Graham Belsham
Co-Investigators / Co-Supervisors
Institution	The Pirbright Institute
Department	The Pirbright Institute Department
Funding type	Research
Value (£)	105,153
Status	Completed
Type	Institute Project
Start date	01/04/2000
End date	31/03/2003
Duration	36 months

Abstract

The translation of picornavirus RNA occurs by internal entry of ribosomes within the RNA sequence rather than at the 5¿ terminus that occurs on cellular mRNAs. Recognition of cellular mRNAs is achieved by interaction between the 5¿ terminal cap-structure and the translation initiation complex eIF4F. This complex comprises eIF4E (which binds the cap itself), eIF4A (a RNA helicase) and eIF4G which acts to bridge between the mRNA and the ribosome. Cleavage of eIF4G occurs early in cells infected with FMDV (and certain other picornaviruses) which blocks cellular protein synthesis but the translation of the viral RNA is maintained. Our work focuses on the mechanism of inhibition of host cell protein synthesis and the mechanism of IRES-directed protein synthesis. We have found that the FMDV 3C protease, in addition to the L protease, is able to induce cleavage of eIF4G and although the sites cleaved are close together the cleavage products can be distinguished. The cleavage of eIF4A is unique to FMDV-infected cells is also mediated by the FMDV 3C protease. Although we know that both L and 3C protease can each modify eIF4G independently we are keen to establish whether the two modifications can occur sequentially on the same eIF4G molecule. If so, it can be anticipated that within FMDV-infected cells the L cleavage will occur first (as it requires very low levels of virus protein production) and will be followed by the 3C mediated process. A high-resolution separation system for eIF4G fragments is being developed to achieve this. To analyse the effect of eIF4A cleavage, we have constructed a series of N-terminal deletion mutants of eIF4A and we are investigating the properties of these molecules (e.g with respect to their ability to interact with eIF4G within cells). We also wish to determine the consequence of FMDV 3C expression on cap-dependent and IRES-directed protein synthesis.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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