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ID 116761
Title Alternative
Discovery of an endoplasmic reticulum proteostasis modulator that enhances insulin production in pancreatic β cells
Author
Sobajima, Mitsuaki Tokushima University
Shigenaga, Akira Tokushima University|Fukuyama University KAKEN Search Researchers
Sakane, Naoki JT
Keywords
ER stress
unfolded protein response
pancreatic β cell
insulin
chemical chaperone
BiP
Content Type
Journal Article
Description
Perturbation of endoplasmic reticulum (ER) proteostasis is associated with impairment of cellular function in diverse diseases, especially the function of pancreatic β cells in type 2 diabetes. Restoration of ER proteostasis by small molecules thus shows therapeutic promise for type 2 diabetes. Here, we report the discovery of a new chemical chaperone-like small molecule, KM04794, that alleviates ER stress using cell-based screening. KM04794 prevented protein aggregation and cell death caused by ER stressors and a mutant insulin protein. We also found that this compound increased intracellular and secreted insulin levels in pancreatic β cells. Chemical biology and biochemical approaches revealed that the compound accumulated in the ER and directly interacted with the ER molecular chaperone BiP. Our data show that this new corrector of ER proteostasis can enhance insulin storage and pancreatic β cell function.
Journal Title
Cell Chemical Biology
ISSN
24519456
Publisher
Elsevier
Volume
29
Issue
6
Start Page
996
End Page
1009.e9
Published Date
2022-02-09
Remark
論文本文は2023-02-09以降公開予定
Rights
© 2022. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
language
eng
TextVersion
その他
departments
Institute of Advanced Medical Sciences
University Hospital
Pharmaceutical Sciences