EDEM1 regulates the insulin mRNA level by inhibiting the endoplasmic reticulum stress-induced IRE1/JNK/c-Jun pathway

Petruta R Flintoaca Alexandru; Gabriela N Chiritoiu; Daniela Lixandru; Sabina Zurac; Constantin Ionescu-Targoviste; Stefana M Petrescu

doi:10.1016/j.isci.2023.107956

EDEM1 regulates the insulin mRNA level by inhibiting the endoplasmic reticulum stress-induced IRE1/JNK/c-Jun pathway

iScience. 2023 Sep 16;26(10):107956. doi: 10.1016/j.isci.2023.107956. eCollection 2023 Oct 20.

Authors

Petruta R Flintoaca Alexandru¹, Gabriela N Chiritoiu¹, Daniela Lixandru², Sabina Zurac³, Constantin Ionescu-Targoviste⁴, Stefana M Petrescu¹

Affiliations

¹ Department of Molecular Cell Biology, Institute of Biochemistry, Romanian Academy, 060031 Bucharest, Romania.
² Department of Biochemistry, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.
³ Department of Physiology, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.
⁴ N. C. Paulescu Institute, Bucharest, Romania.

Abstract

Pancreatic beta cells produce and secrete insulin as a response to rises in blood glucose. Despite the advances in understanding glucose-regulated insulin transcription and translation the mechanisms triggering the synthesis of new insulin molecules are still incompletely described. In this report, we identify EDEM1 as a new modulator of insulin synthesis and secretion. In the presence of EDEM1, INS-1E cells secrete significantly more insulin upon glucose stimulation compared to control cells. We found that overexpression of EDEM1 inhibited the IRE1/JNK/c-Jun pathway, leading to an increase in the insulin mRNA level. Similarly, EDEM1 transduced human islets secreted significantly more insulin upon stimulation. Furthermore, EDEM1 improved insulin secretion restoring normoglycemia and glucose tolerance in diabetic rats. We propose EDEM1 as a regulator of the UPR via IRE1/XBP1s and IRE1/JNK/c-Jun signaling cascades and insulin transcription in pancreatic β-cells, supporting EDEM1 as a potential target for the treatment of diabetes.

Keywords: Biochemistry; Cell biology; Molecular biology; Physiology.