2022年新着論文 18　生体機能学分野、分子生命科学分野、細胞情報学分野から論文が発表されました

Identification of an endoplasmic reticulum proteostasis modulator that enhances insulin production in pancreatic β cells

Cell Chem Biol. 2022 Jun 16;29(6):996-1009.e9. doi: 10.1016/j.chembiol.2022.01.002. Epub 2022 Feb 9.

Authors

Masato Miyake¹, Mitsuaki Sobajima², Kiyoe Kurahashi³, Akira Shigenaga⁴, Masaya Denda⁵, Akira Otaka⁵, Tomohide Saio⁶, Naoki Sakane⁷, Hidetaka Kosako⁸, Seiichi Oyadomari⁹

Affiliations

¹ Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan; Department of Molecular Research, Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. Electronic address: miyake@genome.tokushima-u.ac.jp.
² Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan; Department of Molecular Research, Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan.
³ Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan; Department of Molecular Research, Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan; Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
⁴ Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima, Japan; Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan.
⁵ Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima, Japan.
⁶ Division of Molecular Life Science, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan; Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido, Japan.
⁷ Pharmaceutical Frontier Research Laboratories, JT Inc., Yokohama, Japan.
⁸ Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
⁹ Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan; Department of Molecular Research, Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. Electronic address: oyadomar@genome.tokushima-u.ac.jp.

PMID: 35143772
DOI: 10.1016/j.chembiol.2022.01.002

Abstract

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 shows therapeutic promise for type 2 diabetes. Here, using cell-based screening, we report identification of a chemical chaperone-like small molecule, KM04794, that alleviates ER stress. 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 interacted directly with the ER molecular chaperone BiP. Our data show that this corrector of ER proteostasis can enhance insulin storage and pancreatic β cell function.

Keywords: BiP; ER stress; chemical chaperone; insulin; pancreatic β cell; unfolded protein response.

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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