INIMEC - CONICET   05467
INSTITUTO DE INVESTIGACION MEDICA MERCEDES Y MARTIN FERREYRA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
The protective role of Calcineurin CN-Aβ in ER stress via activation of the Unfolded Protein Responses (UPR) in astrocytes
Autor/es:
CHEN Y., BOLLO M., HOLSTEIN D. AND LECHLEITER J.D.
Lugar:
Mayan Ranch, Texas
Reunión:
Congreso; 2013 San Antonio Nathan Shock Aging Center Conference on Aging"-Stem cells and Aging; 2013
Resumen:
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The
accumulation of unfolded proteins in the Endoplasmic Reticulum (ER) activates a
signal transduction cascade called the Unfolding Protein Response (UPR). The most immediate response is the attenuation of
protein synthesis, initiated by autophosphorylation of PKR-like ER kinase (PERK). Recently, our group reported that
calcineurin (CN) strengthened
the UPR by binding to PERK and enhancing its autophosphorylation (Bollo et al
PLoS One 5
(8):
e11925). Here, we report that CN-Ab protects
astrocytes from ER stress, likely by enhancing autophosphorylation of PERK. First, we found that levels of phosphorylated-PERK
and CN-Ab were significantly
increased in astrocytes within 1 hour of Oxygen and Glucose
Deprivation (OGD). Second, overexpression of CN-Ab significantly increased the
viability of wildtype astrocytes during OGD (1 hr), but not that of PERK-/-
astrocytes. Third, co-immunoprecipitation showed that CN-Ab
preferentially interacted with PERK in ER-stressed astrocytes. Fourth, experiments with recombinant proteins
demonstrated that PERK autophosphorylation and oligomerization were increased
in the presence of CNAb.
Finally, rapamycin-induced dimerization
of CFP-FRB-cytochrome5 (ER anchor) and YFP-FKBP-CN-Ab inside human
astrocytes increased PERK phosphorylation. Taken together, we suggest a novel
physiological function of the classic phosphatase CN-Ab is to bind PERK and enhance the
early UPR. Funded by NIH R01s AG29461-06 and AG007218-25.