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Vol. 20, Issue 11, 2673-2683, June 1, 2009

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Uncoupling Stress Granule Assembly and Translation Initiation Inhibition

Sophie Mokas^*, John R. Mills, Cristina Garreau^*, Marie-Josée Fournier^*, Francis Robert, Prabhat Arya, Randal J. Kaufman, Jerry Pelletier, and Rachid Mazroui^*

*Département de Biologie Médicale, Centre Hospitalier Universitaire de Québec/Centre De Recherche Hôpital Saint-François D'assise, Université Laval, Quebec, Quebec, Canada G1L 3L5; Biochemistry Department and McGill Cancer Center, McGill University, Montreal, Quebec, Canada H3G 1Y6; Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3; and Departments of Biological Chemistry and Internal Medicine and Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109

Submitted October 23, 2008; Revised March 25, 2009; Accepted April 2, 2009
Monitoring Editor: Sandra L. Schmid

Cytoplasmic stress granules (SGs) are specialized regulatory sites of mRNA translation that form under different stress conditions known to inhibit translation initiation. The formation of SG occurs via two pathways; the eukaryotic initiation factor (eIF) 2 phosphorylation-dependent pathway mediated by stress and the eIF2 phosphorylation-independent pathway mediated by inactivation of the translation initiation factors eIF4A and eIF4G. In this study, we investigated the effects of targeting different translation initiation factors and steps in SG formation in HeLa cells. By depleting eIF2, we demonstrate that reduced levels of the eIF2.GTP.Met-tRNAi^Met ternary translation initiation complexes is sufficient to induce SGs. Likewise, reduced levels of eIF4B, eIF4H, or polyA-binding protein, also trigger SG formation. In contrast, depletion of the cap-binding protein eIF4E or preventing its assembly into eIF4F results in modest SG formation. Intriguingly, interfering with the last step of translation initiation by blocking the recruitment of 60S ribosome either with 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamideis or through depletion of the large ribosomal subunits protein L28 does not induce SG assembly. Our study identifies translation initiation steps and factors involved in SG formation as well as those that can be targeted without induction of SGs.

Address correspondence to: Rachid Mazroui (rachid.mazroui{at}crsfa.ulaval.ca)

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