Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes

Rajarshi Ghosh; Kevin Colon-Negron; Feroz R Papa

doi:10.1016/j.molmet.2019.06.012

Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes

Mol Metab. 2019 Sep;27S(Suppl):S60-S68. doi: 10.1016/j.molmet.2019.06.012.

Authors

Rajarshi Ghosh¹, Kevin Colon-Negron¹, Feroz R Papa²

Affiliations

¹ Department of Medicine, University of California, San Francisco San Francisco, CA, 94143-2520, USA; Diabetes Center, University of California, San Francisco San Francisco, CA, 94143-2520, USA; Lung Biology Center, University of California, San Francisco San Francisco, CA, 94143-2520, USA; Quantitative Biosciences Institute, University of California, San Francisco San Francisco, CA, 94143-2520, USA.
² Department of Medicine, University of California, San Francisco San Francisco, CA, 94143-2520, USA; Diabetes Center, University of California, San Francisco San Francisco, CA, 94143-2520, USA; Lung Biology Center, University of California, San Francisco San Francisco, CA, 94143-2520, USA; Quantitative Biosciences Institute, University of California, San Francisco San Francisco, CA, 94143-2520, USA. Electronic address: frpapa@medicine.ucsf.edu.

Abstract

Background: Myriad challenges to the proper folding and structural maturation of secretory pathway client proteins in the endoplasmic reticulum (ER) - a condition referred to as "ER stress" - activate intracellular signaling pathways termed the unfolded protein response (UPR).

Scope of review: Through executing transcriptional and translational programs the UPR restores homeostasis in those cells experiencing manageable levels of ER stress. But the UPR also actively triggers cell degeneration and apoptosis in those cells that are encountering ER stress levels that exceed irremediable thresholds. Thus, UPR outputs are "double-edged". In pancreatic islet β-cells, numerous genetic mutations affecting the balance between these opposing UPR functions cause diabetes mellitus in both rodents and humans, amply demonstrating the principle that the UPR is critical for the proper functioning and survival of the cell.

Major conclusions: Specifically, we have found that the UPR master regulator IRE1α kinase/endoribonuclease (RNase) triggers apoptosis, β-cell degeneration, and diabetes, when ER stress reaches critical levels. Based on these mechanistic findings, we find that novel small molecule compounds that inhibit IRE1α during such "terminal" UPR signaling can spare ER stressed β-cells from death, perhaps affording future opportunities to test new drug candidates for disease modification in patients suffering from diabetes.

Keywords: Apoptosis; Diabetes mellitus; Endoplasmic reticulum stress; Endoribonuclease; Kinase; Small molecule kinase inhibitor; Unfolded protein response.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Diabetes Mellitus / metabolism*
Endoplasmic Reticulum / metabolism*
Endoplasmic Reticulum Stress*
Humans
Insulin-Secreting Cells / metabolism*
Protein Serine-Threonine Kinases / metabolism*
Unfolded Protein Response*

Substances

Protein Serine-Threonine Kinases