Both thapsigargin- and tunicamycin-induced endoplasmic reticulum stress increases expression of Hrd1 in IRE1-dependent fashion

ABSTRACTObjectives: We have investigated the impact of endoplasmic reticulum (ER) stress, which is often implicated in neurodegenerative diseases, on the expression of Hrd1, an E3 ubiquitin ligase that plays a central role in the process of ER-associated degradation (ERAD).Methods: SH-SY5Y neuroblastoma cells, a frequently used model for studying neurotoxicity in dopaminergic neurons and the mechanisms of neurodegeneration associated with Parkinson’s disease, and parental SK-N-SH cells were studied.Results: We demonstrate that ER stress, induced by thapsigargin or tunicamycin, correlates with the increased expression of Hrd1 in both SH-SY5Y and SK-N-SH cells. Inhibition of PERK does not significantly suppress the thapsigargin- or tunicamycin-induced expression of Hrd1. Nevertheless, PERK inhibition has a positive effect on the survival of SH-SY5Y cells treated with thapsigargin but not on those treated with tunicamycin. Inhibition of IRE1 associated with the inhibition of XBP1 splicing does not affect the...