Eukaryotic Stress Granules: The Ins and Outs of Translation

1. Eukaryotic Stress Granules: The Ins and Outs of Translation J. Ross Buchan1,2 and Roy Parker1,2,* 1Howard Hughes Medical Institute 2Department of Molecular and Cellular Biology University of Arizona, Tucson, AZ 85721, USA 2010. 05. 26 Jina Lee

2. Abstract Stress Inhibition of translation initiation Formation of cytoplasmic RNA-protein complexes (mRNP complex) Stress granule -Nontranslating mRNAs -Translation initiation components -Many additional proteins

3. Central dogma of molecular biology Introduction

4. Translation initiation Introduction 43S preinitiation complex (PIC) mRNA activation Scanning AUG recognition Subunit joining Translation elongation Nahum Sonenberg et al. 2009

5. What Are Stress Granules? One Stress response Imparing eIF4E function Phosphorylation of eIF2 Limit the formation of a 43S complex Stress granules typically contain… -Poly(A)+ mRNA, 40S ribosomal subunits, eIF4E, eIF4G, eIF4A, eIF4B, Poly(A)-binding protein(PABP), eIF3, eIF2, RNA helicases, translation and stability regulators, cell signaling factors Translation initiation

6. Stress Granule Assembly Two ◈Protein modification◈ -Phosphorylation -Acetylation -Methylation or the ability to bind methyl groups via tudor domains. ◈Protein-protein interaction domains present on numerous RNA-binding proteins◈ -Dimerization : G3BP -QN-rich prion-like domain self-aggregation promote stress granule assembly glutamine/asparagine-rich domain TIA-1, TIA-R contain conserved QN-rich domain -Heat-shock proteins disassemble prion aggregates inhibition stress granule formation

7. Stress Granule Assembly Two ◈Microtubule network◈ -Dynein : Stress granule assembly Kinesin : Stress granule disassembly -Microtubule disruption stress granule assembly defects impaired mRNP transport -eIF3 is required for stress granule formation. Kinesin Dynein Arsenite TIA-1 facilitate stress granule assembly but not in response to other stresses

8. Disassembly of Stress Granule Three Stress granule disassembly Dissociation of the interactions creating the larger aggregate Degrading the stress granule mRNA pool Removal of mRNAs from stress granules by entry into polysomes ◈ RNA-binding proteins Staufen knockdown stress granule formation Grb7Grb7-ⓟ weaken interactions with other stress granule components FAK Complex autoregulatory loops TIA-R : translational repressor overexpression and knokdown stress granule formation. Cellular conditions Overall concentration Consequence of altered regulation of other stress granule assembly factors

9. Stress Granule Function Four Why do mRNPs aggregate into stress granules? ●Reduce the concentration of those molecules in the cytosol altering the interactions and rates of biochemical reactions MTK1 kinase activity alteration RACK protein sequestration Affects whether cells enter apoptosis Stress Stress granule ●Higher local concentration of components in stress granules increase the rates of mRNP assembly or remodeling driven by these factors mRNA degradation

10. Stress Granule and Apoptosis Five Apoptosis Stress granule Stress is too extreme and the cell is unable to recover. ●Stress granule harbor several apoptosis regulatory factors.

11. Five Stress Granule and Apoptosis ●Apoptosis regulation may link and directly impact upon mRNP regulation. Ribosomal S6 kinase 2(RSK2) and FAST kinase bind QN-rich domain of TIA-1 Antiapoptotic factor Localize in stress granules - TIA-1-promoted apoptosis via phosphorylation - Impair mRNA binding QN-rich domain activity stress granule localization or assembly In summary, the role of stress granules in controlling apoptosis could be to sequester and nullify apoptosis-promoting factors and simultaneously link appropriate mRNP regulation to this decision process.

12. Stress granule Summary 1. Stress response inhibits translation initiation and leads to the formation of cytoplasmic RNA-protein complexes. 5. Stress granule reveal a dynamic cycle of distinct biochemical and compartmentalized mRNPs in cytosol 2. Stress granules contain nontranslating mRNAs, translation initiation components, and many additional proteins. 4. Stress granules have been linked to apoptosis and nuclear processes. 3.Stress granules have been proposed to affect mRNA translation and stability.

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