Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Insulinoma* ; Diabetes Mellitus, Type 1* ; Diabetes Mellitus, Type 2* ; Pancreatic Neoplasms*; Mice ; Animals ; Activating Transcription Factor 4/genetics ; Activating Transcription Factor 4/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Signal Transduction ; Endoplasmic Reticulum Stress ; Apoptosis
    • Abstract:
      Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to β-cell loss in mice. However, the mechanism by which Gsk-3 leads β-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-3β. 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 βTrCP, 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 eIF2α, 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 β-cell death under ER stress conditions.
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    • Grant Information:
      25461357, 16K09752, 19H03710, 20K08887 Grant-in-Aid for Scientific Research; 19H03710 Grant-in-Aid for Scientific Research
    • Contributed Indexing:
      Keywords: activating transcription factor 4; apoptosis; endoplasmic reticulum stress; glycogen synthase kinase 3; pancreatic β-cell
    • Accession Number:
      145891-90-3 (Activating Transcription Factor 4)
      EC 2.7.11.26 (Glycogen Synthase Kinase 3)
      EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
    • Publication Date:
      Date Created: 20221111 Date Completed: 20221114 Latest Revision: 20221117
    • Publication Date:
      20240628
    • Accession Number:
      PMC9657557
    • Accession Number:
      10.3390/ijms232113586
    • Accession Number:
      36362372