Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesised insulin receptors to the cell surface

Brown, Max; Dainty, Samantha; Strudwick, Natalie; Mihai, Adina D.; Watson, Jamie N.; Dendooven, Robina; Paton, Adrienne W.; Paton, James C.; Schröder, Martin

Abstract

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates a signalling network known as the unfolded protein response (UPR). Here we characterise how ER stress and the UPR inhibit insulin signalling. We find that ER stress inhibits insulin signalling by depleting the cell surface population of the insulin receptor. ER stress inhibits proteolytic maturation of insulin proreceptors by interfering with transport of newly synthesised insulin proreceptors from the ER to the plasma membrane. Activation of AKT, a major target of the insulin signalling pathway, by a cytosolic, membrane-bound chimera between the AP20187-inducible FV2E dimerisation domain and the cytosolic protein tyrosine kinase domain of the insulin receptor was not affected by ER stress. Hence, signalling events in the UPR, such as activation of the JNK MAP kinases or the pseudokinase TRB3 by the ER stress sensors IRE1α and PERK, do not contribute to inhibition of signal transduction in the insulin signalling pathway. Indeed, pharmacologic inhibition and genetic ablation of JNKs, as well as silencing of expression of TRB3, did not restore insulin sensitivity or rescue processing of newly synthesised insulin receptors in ER-stressed cells.

Citation

Brown, M., Dainty, S., Strudwick, N., Mihai, A. D., Watson, J. N., Dendooven, R., Paton, A. W., Paton, J. C., & Schröder, M. (2020). Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesised insulin receptors to the cell surface. Molecular Biology of the Cell, 31(23), 2495-2629. https://doi.org/10.1091/mbc.e18-01-0013

• Journal Article Type: Article
• Acceptance Date: Aug 28, 2020
• Online Publication Date: Sep 2, 2020
• Publication Date: 2020-11
• Deposit Date: Sep 2, 2020
• Publicly Available Date: Nov 2, 2020
• Journal: Molecular Biology of the Cell
• Publisher: American Society for Cell Biology
• Peer Reviewed: Peer Reviewed
• Volume: 31
• Issue: 23
• Pages: 2495-2629
• DOI: https://doi.org/10.1091/mbc.e18-01-0013
• Public URL: https://durham-repository.worktribe.com/output/1262533