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Journal of Virology, September 2001, p. 7854-7863, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.7854-7863.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Activity of the Hepatitis A Virus IRES Requires Association between the Cap-Binding Translation Initiation Factor (eIF4E) and eIF4G

Iraj K. Ali,1 Linda McKendrick,2 Simon J. Morley,2 and Richard J. Jackson1,*

Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA,1 and School of Biological Sciences, University of Sussex, Falmer, Brighton BN1 9QG,2 United Kingdom

Received 16 January 2001/Accepted 29 May 2001

The question of whether translation initiation factor eIF4E and the complete eIF4G polypeptide are required for initiation dependent on the IRES (internal ribosome entry site) of hepatitis A virus (HAV) has been examined using in vitro translation in standard and eIF4G-depleted rabbit reticulocyte lysates. In agreement with previous publications, the HAV IRES is unique among all picornavirus IRESs in that it was inhibited if translation initiation factor eIF4G was cleaved by foot-and-mouth disease L-proteases. In addition, the HAV IRES was inhibited by addition of eIF4E-binding protein 1, which binds tightly to eIF4E and sequesters it, thus preventing its association with eIF4G. The HAV IRES was also inhibited by addition of m7GpppG cap analogue, irrespective of whether the RNA tested was capped or not. Thus, initiation on the HAV IRES requires that eIF4E be associated with eIF4G and that the cap-binding pocket of eIF4E be empty and unoccupied. This suggests two alternative models: (i) initiation requires a direct interaction between an internal site in the IRES and eIF4E/4G, an interaction which involves the cap-binding pocket of eIF4E in addition to any direct eIF4G-RNA interactions; or (ii) it requires eIF4G in a particular conformation which can be attained only if eIF4E is bound to it, with the cap-binding pocket of the eIF4E unoccupied.

* Corresponding author. Mailing address: Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd., Cambridge CB2 1GA, United Kingdom. Phone: (44) 1223-333682. Fax: (44) 1223- 766002. E-mail: rjj{at}mole.bio.cam.ac.uk.

Journal of Virology, September 2001, p. 7854-7863, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.7854-7863.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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