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

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.

Figure 1

‘A’- to ‘T’-UPR conversions may promote β-cell death in diabetes. During ER stress, adaptive UPR outputs maintain cellular homeostasis. If ER stress remains unmitigated, terminal UPR signaling drives destructive outputs culminating in β-cell apoptosis. Declining β-cell mass elevates workload/ER stress in remaining β-cells in vicious cycles promoting diabetes. These principles may be a unifying feature in monogenetic and polygenetic forms of diabetes (both rare and common). In various UPR gene mutations, loss of function of critical UPR components (e.g., PERK) dysregulates the pathway leading to infantile diabetes. Gain-of-function proteotoxicity accompanies mutant proinsulin expression in the MIDY syndrome caused by the (C96Y) Akita variant. In T1D, islet immune cell infiltration elevates ER stress in β-cells. Peripheral insulin resistance elevates β-cell overwork in T2D. It is conceivable that similar events that occur in the murine models drive β-cell degeneration in human T1D and T2D.

Figure 2

The three first responders of the UPR are diagrammed. Upon activation under ER stress, three sensors, IRE1α, PERK, and ATF6 send intracellular signals that allow the cell to either adapt or commit apoptosis.

Figure 3

IRE1α acts as a homeostatic-apoptotic switch in response to ER stress. (A) Homeostatic XBP1 splicing progresses to apoptotic mRNA decay if ER stress is unresolved, (B).

Figure 4

Through IRE1α RNase hyperactivation — and ER-localized mRNA and miR decay — ER stress can secondarily morph to cause oxidative stress (loss of PRDX4), loss of differentiated cell identity (decreases in insulin mRNA and protein), inflammation (TXNIP induction), proliferation blocks, and pyroptotic/apoptotic cell death. See text for details.

Figure 5

KIRA8 dose-dependently breaks IRE1α homo-oligomers and allosterically reduces RNAse hyperactivation. Because lower-order species suffice for adaptive XBP1 mRNA splicing, sub-complete IRE1α inhibition with KIRAs selectively attenuates the T-UPR under high/chronic ER stress.