Eukaryotic Stress Granules:The Ins and Outs of Translation

2010. 05. 262010. 05. 26

Jina Lee

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

Abstract

Stress

Inhibition of translation initiation

Formation of cytoplasmic RNA-protein complexes

Stress granule

-Nontranslating mRNAs

-Translation initiation components

-Many additional proteins

(mRNP complex)

IntroductionCentral dogma of molecular biologyCentral dogma of molecular biology

IntroductionTranslation initiationTranslation initiation

Nahum Sonenberg et al. 2009

43S preinitiation complex (PIC)

mRNA activation

Scanning

AUG recognition

Subunit joining

Translation elongation

One What Are Stress Granules?What Are Stress Granules?

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

Stress response

Imparing eIF4E function

Phosphorylation of eIF2

Limit the formation of a 43S complex

Translation initiation

Stress Granule AssemblyStress Granule Assembly

◈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

Two

Stress Granule AssemblyStress Granule AssemblyTwo

◈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.

Dynein Kinesin

Arsenite TIA-1 facilitate stress granule assembly but not in response to other

stresses

Three Disassembly of Stress GranuleDisassembly of Stress Granule

Dissociation of the interactions creating the larger aggregate

Degrading the stress granule mRNA pool

Removal of mRNAs from stress granules by entry into polysomes

Stress granule disassembly

◈ RNA-binding proteins

Staufen knockdown stress granule formation

Grb7 Grb7-ⓟ 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

Four Stress Granule FunctionStress Granule Function

Stress

granule

mRNA degradation

Why do mRNPs aggregate into stress granules?

●Reduce the concentration of those molecules in the cytosol

altering the interactions and rates of biochemical reactions

StressRACK protein

sequestration

MTK1 kinase activity

alteration

Affects whether cells

enter apoptosis

●Higher local concentration of components in stress granules

increase the rates of mRNP assembly or remodeling driven by

these factors

Five Stress Granule and ApoptosisStress Granule and Apoptosis

Stress granule Apoptosis

Stress is too extreme and the cell is unable to recover.

● Stress granule harbor several apoptosis regulatory factors.

Five Stress Granule and ApoptosisStress 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.

Summary

Stress

granule

1. 1. Stress response inhibits Stress response inhibits translation initiation and leads translation initiation and leads to the formation of cytoplasmic to the formation of cytoplasmic

RNA-protein complexes.RNA-protein complexes.

2.2. Stress granules contain Stress granules contain nontranslating mRNAs, nontranslating mRNAs,

translation initiation translation initiation components, and many components, and many

additional proteins. additional proteins.

3.3. Stress granules have been Stress granules have been proposed to affect mRNA proposed to affect mRNA translation and stability.translation and stability.

5.5. Stress granule reveal a Stress granule reveal a dynamic cycle of distinct dynamic cycle of distinct

biochemical and biochemical and compartmentalized compartmentalized mRNPs in cytosolmRNPs in cytosol

4.4. Stress granules Stress granules have been linked to have been linked to

apoptosis and apoptosis and nuclear processes.nuclear processes.

Thank you~!!