ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes

Abstract

Components of the unfolded protein response (UPR) modulate beta cell inflammation and death in early type 1 diabetes (T1D). The UPR is a mechanism by which cells react to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). It aims to restore cellular homeostasis, but in case of chronic or overwhelming ER stress the persistent activation of the UPR triggers apoptosis, contributing to the loss of beta cells in both T1D and type 2 diabetes. It remains to be determined how and why the transition from 'physiological' to 'pathological' UPR takes place. A key component of the UPR is the ER transmembrane protein IRE1α (inositol-requiring enzyme 1α). IRE1α activity is modulated by both intra-ER signals and by the formation of protein complexes at its cytosolic domain. The amplitude and duration of IRE1α signaling is critical for the transition between the adaptive and cell death programs, with particular relevance for the activation of the pro-apoptotic c-Jun N-terminal kinase (JNK) in beta cells. In the present review we discuss the available information on IRE1α-regulating proteins in beta cells and their downstream targets, and the important differences observed between cytokine-induced UPR in human and rodent beta cells.

Keywords: Apoptosis; ER stress; IRE1α; c-Jun N-terminal kinase; cytokines; type 1 diabetes.

Figure 1.

Role of the IRE1α-interacting proteins NMI and UBD in cytokine-induced beta cell apoptosis. The pro-inflammatory cytokines IL-1β + IFN-γ induce ER stress and activation of the IRE1α/JNK/c-Jun pathway that contributes to beta cell apoptosis. In parallel, IL-1β + IFN-γ induce the expression of NMI and UBD that bind to IRE1α and negatively regulate the phosphorylation of JNK, providing a negative feedback on this pro-apoptotic pathway. This feedback may prevent beta cell death in the context of mild and transitory local inflammation, but will not prevent beta cell death during a protracted autoimmune assault. The figure is based on findings from Brozzi F et al. (40) and Brozzi F et al., submitted for publication.

Figure 2.

Proposed models for ER stress-induced apoptosis in cytokine-treated rat and human beta cells. A: IL-1β + IFN-γ, via NO production and consequent SERCA-2b inhibition, cause severe ER Ca²⁺ depletion in rat beta cells. NO also inhibits XBP1s protein expression, depriving these cells of a relevant adaptive mechanism. B: In human beta cells IL-1β + IFN-γ induce ER stress via mechanisms that are independent of NO production. The nature of these mechanisms remains to be clarified, but they may be related to inhibition of other Ca²⁺ channels, excessive insulin secretion, and over-expression of MHC class I and related proteins. The persistent activation of the IRE1α/JNK and PERK/CHOP pathways contributes to apoptosis in both rat and human beta cells.

Figure 3.

Cytokine-induced decrease in XBP1s protein expression is dependent on NO production in INS-1E and MIN6 cells. INS-1E cells (A) and MIN6 cells (B) were left untreated (CTRL) or treated with cytokines (as indicated), alone or in combination with 1 mmol/L of L-NMMA, for 24 h. A representative blot for XBP1s and tubulin, and the densitometric measurement of n = 3–4 experiments are shown. The Western blot data were normalized by the highest value considered as 1.