Abstract
Accumulation of misfolded proteins in the endoplasmic reticulum (ER), defined as ER stress, results in activation of the unfolded protein response (UPR). UPR activation is commonly observed in neurodegenerative diseases. ER stress can trigger unconventional secretion mediated by Golgi reassembly and stacking proteins (GRASP) relocalization in cell lines. Here we study the regulation of GRASP55 by the UPR upon pharmacological induction of ER stress in primary mouse neurons. We demonstrate that UPR activation induces mRNA and protein expression of GRASP55, but not GRASP65, in cortical neurons. UPR activation does not result in relocalization of GRASP55. UPR-induced GRASP55 expression is reduced by inhibition of the PERK pathway of the UPR and abolished by inhibition of the endonuclease activity of the UPR transducer IRE1. Expression of the IRE1 target XBP1s in the absence of ER stress is not sufficient to increase GRASP55 expression. Knockdown of GRASP55 affects neither induction nor recovery of the UPR. We conclude that the UPR regulates the unconventional secretion factor GRASP55 via a mechanism that requires the IRE1 and the PERK pathway of the UPR in neurons.
| Original language | English |
|---|---|
| Article number | 1567 |
| Pages (from-to) | 1-12 |
| Number of pages | 12 |
| Journal | Scientific Reports |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 7 Feb 2019 |
Funding
We thank Robbert Zalm and Rob Zwart for the cloning of the ATF6 and XBP1s constructs and generation of lentiviral expression vectors and Fabian Bangel for assisting with qPCR analysis. For critical reading of the manuscript and stimulating discussions we thank the Molecular Neurodegeneration group (Functional Genomics, VU university, Amsterdam). This research was supported by the ZonMW Memorabel project 733050101 (Deltaplan Dementie, co-funded by Alzheimer Nederland).
| Funders | Funder number |
|---|---|
| ZonMw | 733050101 |
