Transcript Stress Granule and Apoptosis

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
Abstract
Stress
Inhibition of translation initiation
Formation of cytoplasmic RNA-protein complexes
(mRNP complex)
Stress granule
-Nontranslating mRNAs
-Translation initiation components
-Many additional proteins
Introduction
Central dogma of molecular biology
Initiation
-A ribosome attaches to the mRNA
Elongation
-tRNA brings the corresponding amino
acid to each codon
Termination
-Reading of the final mRNA codon
Introduction
Translation initiation
43S preinitiation complex (PIC)
mRNA activation
Scanning
AUG recognition
Subunit joining
Translation elongation
Nahum Sonenberg et al. 2009
One
What Are Stress Granules?
Decreased
translation initiation
rate
Addition of drugs
blocking tranalation
initiation
Stress
granule
Knockdown of
specific initiation
factors
Overexpression of
RNA-binding
proteins
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
Two
Stress Granule Assembly
Protein-protein
interaction
domains
◈Protein modification◈
-Phosphorylation
Protein
modification
Microtubule
network
-Acetylation
-Methylation or the ability to bind methyl groups
via tudor domains.
Stress
granule
assembly
◈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 Assembly
◈Microtubule network◈
-Dynein : Stress granule assembly
Kinesin : Stress granule disassembly
-Microtubule disruption
Kinesin
Dynein
stress granule assembly defects
impaired mRNP transport
-eIF3 is required for stress granule formation.
• Overexpression or depletion of many factors
Stress granule
components likely
interact in multiple and
stress-specific manners
• Most factors localize very transiently
• Stress granule size and shape varies over time
• Assembly factors important under one stress condition
Arsenite
TIA-1 facilitate stress granule assembly but not in response to other stresses
Disassembly of Stress Granule
Three
Dissociation of the interactions creating the larger aggregate
Degrading the stress granule mRNA pool
Stress granule disassembly
Removal of mRNAs from stress granules by entry into polysomes
◈ RNA-binding proteins
Staufen knockdown
Grb7
FAK
stress granule formation
weaken interactions with other stress granule components
Grb7-ⓟ
Complex
TIA-R : translational repressor
autoregulatory
overexpression and knokdown stress granule formation.
loops
Cellular conditions
Overall concentration
Consequence of altered regulation of other stress granule assembly factors
Four
Stress Granule Function
Why do mRNPs aggregate into stress granules?
●Reduce the concentration of those molecules in the cytosol
Decrease
of global
translation
•Numerous stress granule
components are
translational repressors
altering the interactions and rates of biochemical reactions
Stress
Stress
RACK protein
MTK1 kinase activity
Affects whether cells
sequestration
alteration
enter apoptosis
granule
Stabilize
mRNAs
•Stress responses inhibit
mRNA adenylation
mRNA degradation
●Higher local concentration of components in stress granules
increase the rates of mRNP assembly or remodeling driven by
these factors
Five
Stress Granule and Apoptosis
Stress granule
Apoptosis
Stress is too extreme and the cell is unable to recover.
● Stress granule harbor several apoptosis regulatory factors.
apoptosis-inducing
stress
Modest stress
MTK1 and RACK1
activation
RACK1 sequestion
apoptosis
Do not apoptosis
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.
Summary
1. Stress response inhibits
5. Stress granule reveal a
dynamic cycle of distinct
biochemical and
compartmentalized mRNPs
in cytosol
translation initiation and leads to
the formation of cytoplasmic RNAprotein complexes.
2. Stress granules contain
Stress granule
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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