Unique ER Stress Mechanisms in β Cells Limit the Translation Potential of Therapies Targeting eIF2α

Endoplasmic reticulum (ER) stress is established as one of the key mechanism mediating β-cell dysfunction and eventually β-cell destruction in type 2 diabetes (1). There are multiple stresses that have been linked to β-cell ER stress and related states. For example, prolonged exposure of β cells to the combination of hyperglycemia and elevated circulating free fatty acids, termed glucolipotoxicity, activates an ER stress response in β cells that, if unresolved, leads to impaired insulin secretion and ultimately apoptosis and/or other forms of programmed cell death (2, 3). In β cells and in other cell types, ER stressors result in the binding of molecular chaperone BiP (an immunoglobulin heavy-chain binding protein) to the accumulating unfolded and misfolded proteins in the lumen of the ER, thereby initiating a canonical unfolded protein response (UPR). The UPR, as we collectively understand it, consists of three signaling branches: one involving the inositol-requiring protein 1α–X-box binding protein 1, one involving the activating transcription factor 6α, and one involving the protein kinase R-like ER kinase (PERK)–eukaryotic translation initiation factor 2α (eIF2α) (4). From the cell’s perspective, the aim of UPR activation is to resolve protein misfolding in the ER by increasing folding capacity, to promote protein transport, and to activate the ER-associated protein degradation to clear out damaged proteins. However, if ER stress is not resolved, the UPR then initiates an apoptotic signaling cascade, such as induction of CCAAT/enhancer-binding protein homologous protein, the product of the DDIT3 gene (5). Another key step in the UPR response is attenuation of general protein translation to limit the amount of incoming protein entering the ER. Notwithstanding, at the same time, the cell’s protein synthesis machinery allows translation of a specific subset of messenger RNAs (mRNAs) important for resolution of ER stress (6). The best studied mechanism for modulating mRNA translation in the context of ER stress is the PERK-dependent phosphorylation of eIF2α, a protein that, when phosphorylated, cannot deliver the Met-charged initiator transfer RNA to the P site of the small ribosomal subunit to initiate translation (7). The negative feedback loop consisting of PERK-dependent induction of growth arrest and DNA damage-inducible protein 34 (GADD34) mediates the recovery from translation repression by catalyzing dephosphorylation of eIF2α (8). Our current knowledge, mostly derived from studies in non-β cells, presents a complex picture of ER stress that still has unanswered questions, including whether treatments designed to intervene at the level of protein translation might have therapeutic benefit at the level of the endocrine pancreas. It has been suggested that targeting the PERK-eIF2α pathway may be a way to reduce ER stress and protect cell types relevant to diabetes. Studies in HeLa and PC12 cell lines reported decreased apoptosis during ER stress (9, 10). However, the PERK-eIF2α pathway has been long recognized as a “double-edged sword” regulating two contrasting functions function in β cells (11, 12). On one hand, it mediates a key step in UPR during ER stress, as described previously. On the other hand, it has an important physiological role in regulating insulin synthesis in response to the perturbations in glucose levels (11). Specifically, a postprandial rise in blood glucose stimulates dephosphorylation of eIF2α by GADD34 and the assembly of the translational ternary complex, eIF2-guanosine triphosphate Met-charged initiator transfer RNA, which initiates translation of insulin mRNA. When blood glucose levels decrease, PERK-mediated phosphorylation of eIF2α coordinately attenuates mRNA translation, prevents oxidative stress, and optimizes ER protein folding for decreased demand in insulin production (11). However, in β cells, ER stress is not only found under extreme pathophysiological conditions. We recently demonstrated that moderate ER stress is a default state for pancreatic β cells in vivo because of the enormous load on the ER associated with demand for proinsulin mRNA translation (13). When this demand was reduced by insulin gene knockout, we observed a decrease in eIF2α phosphorylation levels and a significant reduction in ER stress markers (13). Moreover, it has also been shown that subthreshold ER stress via the activating transcription factor 6 pathway drives insulin demand–induced β-cell proliferation (14). Therefore, ER stress is integral to the regulation of β-cell function in both physiological and pathophysiological conditions. In this issue of Endocrinology, Abdulkarim et al. (15) tested whether increased phosphorylation of eIF2α during lipotoxic ER stress would affect function and viability of β cells and explored possibility of using an approved antihypertensive drug that targets the PERK-eIF2α branch of the UPR as a treatment for diabetes. Specifically, Abdulkarim et al. used guanabenz, a GADD34 inhibitor that inhibits eIF2α dephosphorylation, to precisely study the importance of eIF2α phosphorylation state during lipotoxic ER stress. Guanabenz has been shown to protect HeLa cells undergoing ER stress from apoptosis by delaying translational recovery and preventing induction of proapoptotic CCAAT/enhancer-binding protein homologous protein (10). Surprisingly, Abdulkarim et al. found that both in vitro and in vivo guanabenz potentiated ER-mediated apoptosis in β cells in the context of lipotoxic conditions. A previous report from this group using another selective inhibitor of eIF2α dephosphorylation, salubrinal, similarly showed that it potentiates fatty acid–induced ER stress and apoptosis (16), despite being cytoprotective during ER stress in other cell types (9). The current article, together with previous findings, emphasize the uniqueness of ER stress and the UPR in β cells. One of the important characteristics of ER stress in β cells, also described in Abdulkarim et al., is a lack of translational recovery (16). This feature is in clear contrast to what many investigators have observed in studies of other cell types (10, 17). This might explain why inhibition of eIF2α dephosphorylation promotes survival of stressed hippocampal and epithelial (18), but does not protect β cells. Mice conditionally expressing a phosphorylation-deficient mutant of eIF2α in β cells show a severe diabetic phenotype resulting from unregulated translation of insulin mRNA, which in turn causes increased oxidative damage and β-cell apoptosis (19). Similarly, deletion of the upstream regulator PERK in adult mice causes hyperglycemia associated with β-cell apoptosis because of an accumulation of immature insulin and massive expansion of the ER (20). In this article, Abdulkarim et al. (15) showed that short-term administration of guanabenz to high-fat diet-fed mice increased basal insulin secretion and increased cell death in pancreatic islets. Interestingly, short-term administration of guanabenz to mice on a regular chow diet also caused increased fasting blood glucose levels and insulin resistance. These findings confirm that regulation of eIF2α phosphorylation is very important for proper β-cell function. Physiologically, the levels of insulin biogenesis and secretion are partially determined by blood glucose fluctuations and by PERK-dependent phosphorylation of eIF2α, which, in turn, help adjust the amount of protein delivered into the ER lumen (8). Taken together with other work in the field, the article by Abdulkarim et al. (15) makes an important contribution to our understanding of UPR signaling in β-cell physiology and how tight regulation of translation is a key for β-cell function and viability. In various other cell types, sustained phosphorylation of eIF2α during ER stress increases cell viability, but for β cells prolonged phosphorylation of eIF2α during lipotoxic ER stress is “too much of a good thing” (Figure 1). Until we understand all the details of translational regulation during ER stress in β cells, we should be cautious in targeting the PERK-eIF2α pathway for improving β-cell function in diabetes. Recent identification of alternative translation initiation factors active during ER stress might help address this issue in the future (21, 22). Finally, findings by Abdulkarim et al. have direct clinical implications because guanabenz is used as an antihypertensive drug and therefore patients should be more carefully evaluated for possible hyperglycemic side effects. Inhibition of eIF2α dephosphorylation during ER stress enhances cell viability in various cell types, but potentiates death of β cells during lipotoxic ER stress. PERK-mediated phosphorylation of eIF2α in β cells and other cell types and effect of inhibitors of eIF2α dephosphorylation on cell viability during ER stress. eukaryotic translation initiation factor 2α endoplasmic reticulum DNA damage-inducible protein 34 messenger RNA protein kinase R-like ER kinase unfolded protein response. Disclosure Summary: The authors have nothing to disclose.

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