Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/ijms232113586
Keywords
apoptosis; endoplasmic reticulum stress; glycogen synthase kinase 3; activating transcription factor 4; pancreatic beta-cell
Funding
- Takeda Science foundation [25461357, 16K09752, 19H03710, 20K08887]
- Banyu Life Science foundation
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Endoplasmic reticulum stress is a key pathogenic factor in type 1 and 2 diabetes. Gsk-3 inhibition prevents proteasomal degradation of ATF4 and alleviates apoptosis by regulating phosphorylation of ATF4-S214. Mechanistically, Gsk-3 inhibition modulates transcription targets of ATF4 and facilitates dephosphorylation of eIF2 alpha under ER stress.
Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to beta-cell loss in mice. However, the mechanism by which Gsk-3 leads beta-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and insulinoma cells. We used insulinoma cells derived from Akita mice as a model of genetic ER stress. Gsk-3 activity was blocked by treating with Gsk-3 inhibitors or by introducing catalytically inactive Gsk-3 beta. Gsk-3 inhibition prevented proteasomal degradation of activating transcriptional factor 4 (ATF4) and alleviated apoptosis. We found that ATF4-S214 was phosphorylated by Gsk-3, and that this was required for a binding of ATF4 with beta TrCP, which mediates polyubiquitination. The anti-apoptotic effect of Gsk-3 inhibition was attenuated by introducing DN-ATF4 or by knockdown of ATF4. Mechanistically, Gsk-3 inhibition modulated transcription targets of ATF4 and in turn facilitated dephosphorylation of eIF2 alpha, altering the protein translational dynamism under ER stress. These observations were reproduced in the Akita mouse-derived cells. Thus, these results reveal the role of Gsk-3 in the regulation of the integrated stress response, and provide a rationale for inhibiting this enzyme to prevent beta-cell death under ER stress conditions.
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