INVESTIGADORES
MARTINEZ TOSAR Leandro Julian
congresos y reuniones científicas
Título:
Staufen modulates the assembly of stress granules
Autor/es:
MARTÍNEZ TOSAR, LEANDRO J.; DESBATS, MARÍA ANDREA AND BOCCACCIO, GRACIELA L
Lugar:
Huerta Grande, Córdoba - Argentina
Reunión:
Taller; 8vo. Taller Argentino de Neurociencias; 2006
Resumen:
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Normal
oxidative metabolism in the brain represents a continuous potential source of
oxidative stress, a hazardous chemical state to which nerve cells are
particularly sensitive. Moreover, oxidative stress is associated to several
pathological conditions of the nervous system such us multiple sclerosis,
Alzheimer´s and Parkinson´s diseases, as well as events of reperfusion
following ischemia. Several stress conditions (including oxidative stress, UV
irradiation, heat shock, and aminoacid deprivation, among others) are known to
trigger a plethora of cellular adaptations collectively known as stress response, in many cell types.
Under stress, translation ceases for most mRNAs, which become incorporated into
large cytoplasmic ribonucleoparticles known as stress granules (SG) where they
are believed to be selectively targeted for stabilization, decay, or redirected
to resume normal translation. Typical components of SG are the 48S
pre-initiation complex, PABP, the nucleo-cytoplasmic shuttling proteins TIAR
and TIA-1, the mRNA stabilizing protein HuR, and the mRNA destabilizing protein
Tristetraprolin, among others.
Previous
and recent results from our lab show that the double-stranded RNA-binding
protein Staufen1, normally associated to polysomes, accumulates in SG induced
by different stressors and in several cell types, including primary
oligodendrocytes and neurons (Thomas et
al. MolBiolCell 2005, Baez and Boccaccio, unpublished). However, the role
of Staufen in SG physiology remains unknown.
To address
this issue, we have conducted transient oxidative or ER stress in cell lines
where Staufen levels had been manipulated by RNA interference-mediated knock
down or by overexpression.
We found
that Staufen-depleted cells display facilitated SG assembly under oxidative
stress (induced by sodium arsenite) and endoplasmic reticulum stress (induced
by thapsigargin). In these same conditions, Staufen1-EGFP overexpression
inhibits SG formation in a dose-dependent manner, an effect much weaker in Staufen2
overexpressing cells, and not observed with EGFP alone. Furthermore, Staufen1
overexpression also inhibits formation of cytoplasmic foci specialized in mRNA
degradation known as P-bodies. Interestingly, P-bodies are known to recede upon
polysome stabilization.
High
Staufen levels do not interfere with phosphorylation of eukaryotic initiation
factor 2a, a well known trigger of SG assembly under
different sorts of stress, suggesting that Staufen-mediated SG inhibition takes
place at a downstream step in the stress response cascade.
Finally,
overexpression of Staufen1 deletional constructs allowed us to map the SG
inhibitory activity to the N-terminal portion of the protein.
These
results suggest a potential role for Staufen1 in the regulation of SG assembly
under oxidative stress. We hypothesize that Staufen shifts the balance between
polysomes and stress granules, stabilizing polysomes and inhibiting SG
assembly.