Calcineurin regulates PERK autophosphorlation in astrocytes under ER stress.

BOLLO M, AIME S, CHEN Y, PAREDES M DEBORAH H AND LECHLEITER J

Congreso; Segunda Sociedad Conjunta de la XXV Sociedad Argentina de Neurociencia (SAN) y el XII Taller Argentino de Neurociencias (TAN); 2010

The accumulation of unfolded proteins into the Endoplasmic Reticulum (ER) activates a signal transduction cascade called Unfolding Protein Response (UPR), which attempts to restore homeostasis in the organelle. (PKR)-like-ER kinase (PERK) is an early stress response transmembrane protein that is generally inactive due to its association with the chaperone BIP. During ER stress, BIP is tritrated by the unfolded protein, leading PERK activation and phosphorylation of eukaryotic initiation factor-2 alpha (eIF2alpha), which attenuates protein synthesis. We demonstrated that calcineurin-A/B(CN-A/B), an heterotrimeric Ca2+ phosphatase, associates with PERK, increasing its auto-phosphorylation and significantly enhancing inhibition of protein translation and cell viability in Xenopus oocytes. Moreover, we report that CN-A/B and PERK interaction is significantly increased after Oxygen and Glucose Deprivation (OGD) treatment in astrocytes. These cells deficient in CN-Abeta isoform have constitutive active UPR. OGD treatment did not further increase cell death or eIF2alpha phosphorylation in CN-Abeta-/- cells, but did so in both CN-Aalpha -/- and wild-type controls. Our finding indicates that the protective role of CN observed in Xenopus oocytes is extended to astrocytes stressed by OGD.