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Molecular and Cellular Biology, March 2008, p. 1429-1442, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01512-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Novel Mechanism for the Control of Translation Initiation by Amino Acids, Mediated by Phosphorylation of Eukaryotic Initiation Factor 2B{triangledown}

Xuemin Wang1,2 and Christopher G. Proud1,2*

Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom,1 Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada2

Received 20 August 2007/ Returned for modification 26 September 2007/ Accepted 16 December 2007

Eukaryotic initiation factor 2B (eIF2B) plays a key role in controlling the initiation of mRNA translation. eIF2B is heteropentamer whose catalytic ({varepsilon}) subunit promotes GDP/GTP exchange on eIF2. We show here that depriving human cells of amino acids rapidly results in the inhibition of eIF2B, independently of changes in eIF2 phosphorylation. Although amino acid deprivation also inhibits signaling through the mammalian target of rapamycin complex 1 (mTORC1), the inhibition of eIF2B activity by amino acid starvation is independent of mTORC1. Instead, amino acids repress the phosphorylation of a novel site in eIF2B{varepsilon}. We identify this site as Ser525, located adjacent to the known phosphoregulatory region in eIF2B{varepsilon}. Mutation of Ser525 to Ala abolishes the regulation of eIF2B and protein synthesis by amino acids. This indicates that phosphorylation of this site is crucial for the control of eIF2B and protein synthesis by amino acids. These findings identify a new way in which amino acids regulate a key step in translation initiation and indicate that this involves a novel amino acid-sensitive signaling mechanism.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Phone: (604) 827-3923. Fax: (604) 822-5227. E-mail: cgpr{at}interchange.ubc.ca

{triangledown} Published ahead of print on 26 December 2007.

Molecular and Cellular Biology, March 2008, p. 1429-1442, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01512-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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