Journal Article

ASK1 Overexpression Accelerates Paraquat-Induced Autophagy via Endoplasmic Reticulum Stress

Mireia Niso-Santano, José M. Bravo-San Pedro, Rubén Gómez-Sánchez, Vicente Climent, Germán Soler, José M. Fuentes and Rosa A. González-Polo

in Toxicological Sciences

Volume 119, issue 1, pages 156-168
Published in print January 2011 | ISSN: 1096-6080
Published online October 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq313
ASK1 Overexpression Accelerates Paraquat-Induced Autophagy via Endoplasmic Reticulum Stress

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Apoptosis signal-regulating kinase 1 (ASK1) is activated by various types of stress, including, endoplasmic reticulum (ER) stress. ER stress–induced ASK1 activation could play an important role both in neuronal apoptosis and an autophagic response in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease. The mechanism by which ASK1 executes apoptosis and/or autophagy under ER stress is still unclear. We have addressed this question using SH-SY5Y cells overexpressing wild-type (WT) ASK1. We show an important autophagic response and an acceleration of the paraquat (PQ)-induced autophagy with hallmarks as accumulation of autophagic vacuoles, activation of beclin-1, accumulation of LC3 II, p62 degradation, and mammalian target of rapamycin dephosphorylation. Inhibition of autophagy caused an exacerbation of the apoptosis induced by WT ASK1 overexpression with or without PQ. These data support the idea that the autophagic response could have a protector role. We found also an increase in the phosphorylation of the proteins such as IRE1 and eIF2α in response to both the overexpression of WT ASK1 and pesticide exposure. These data suggest that the WT ASK1 overexpression–induced autophagy is an event that occurs in parallel with ER stress activation. The importance of ER stress in the autophagy induced by ASK1 and/or PQ was confirmed with salubrinal, a selective inhibitor of eIF2α dephosphorylation. In conclusion, we report that PQ induces an early ER stress response that is correlated with the activation of autophagy as a protective response, which is accelerated in cells that overexpress WT ASK1. However, when the toxic stimuli remain, the cell eventually succumbs to apoptosis.

Keywords: ASK1; autophagy; reticulum stress; paraquat; Parkinson's disease

Journal Article.  6601 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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