Uncoupling Stress Granule Assembly and Translation Initiation Inhibition

Apr 17, 2009Molecular biology of the cell

Separating stress granule formation from the slowdown of protein production

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Abstract

Reduced levels of eIF2alpha, eIF4B, eIF4H, or polyA-binding protein can induce stress granule (SG) formation in HeLa cells.

Stress granules form as specialized sites of mRNA translation regulation during stress.
Two pathways contribute to stress granule formation: one dependent on eIF2alpha phosphorylation and another independent of it.
Depleting eIF2alpha leads to lower levels of translation initiation complexes, which is sufficient to trigger SGs.
Targeting eIF4B, eIF4H, or polyA-binding protein also results in SG formation.
Depletion of the cap-binding protein eIF4E causes only modest SG formation.
Blocking the recruitment of the 60S ribosome does not lead to SG assembly.

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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) 2alpha phosphorylation-dependent pathway mediated by stress and the eIF2alpha 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 eIF2alpha, 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.

Uncoupling Stress Granule Assembly and Translation Initiation Inhibition

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