Differences in endoplasmic reticulum stress signalling kinetics determine cell survival outcome through activation of MKP-1.

Endoplasmic reticulum (ER) stress signalling pathways are involved in various alterations of the central nervous system such as neurodegenerative diseases or ischemia. The current mechanisms linking ER stress activation to neuronal cell fate upon chronic or acute stresses remain however to be fully understood. Recent studies have associated ER stress severity and the relative activation levels of certain output pathways to influence cell-fate decisions. In the present report, to further test the impact of ER stress severity on neuronal survival, we designed an experimental system recapitulating acute and chronic stress in cerebellar granule neurons (CGNs) and c17.2 mouse neural stem cells (NSCs). Two well characterized ER stress inducers, tunicamycin (TM) and dithiothreitol (DTT), were used to induce "slow motion" and "fast motion" stresses, respectively. We show that the duration of JNK activation is critical for cell survival upon ER stress. TM-induced transient JNK activation is a protective event in CGNs and c17.2 NSCs via the phosphorylation of BAD, while DTT-induced prolonged JNK activation mediates pro-apoptotic signalling. In addition, we demonstrate that ER stress mediated MKP-1/DUSP1 expression regulates JNK activation kinetics. MKP-1 phosphorylation and protein expression level are differentially altered upon TM and DTT treatment. Increased MKP-1 protein stability via its phosphorylation on ser359 induced by TM accounts for transient JNK activation and the resulting cell survival in CGNs and c17.2 NSCs subjected to ER stress. These results suggest that MKP-1 plays a pivotal role in ER stress-induced cell apoptosis through regulating JNK-BAD signalling.