Modulation of Protein Synthesis by eIF2α Phosphorylation Protects Cell from Heat Stress-Mediated Apoptosis

Abstract

Global warming poses a considerable threat to human health, necessitating a proper understanding of mechanisms underlying cell death in the pathogenesis of heat-related diseases. Although mechanisms governing cytoplasmic response to heat are well understood, processes regulating cellular response to disruption of proteostasis in the endoplasmic reticulum (ER) due to heat stress remain unclear. The current study reveals that hyperthermic conditions may lead to a disturbance of ER homeostasis, also known as ER stress. Subsequent activation of the unfolded protein response (UPR) resulted in concomitant induction of cell death. Among the three UPR signaling pathways, the eIF2α phosphorylation pathway, and not the IRE1α/ATF6α pathways, is likely the main contributor to cell death under heat stress. Considering the role of eIF2α in translational control, we investigated the protective effect of translation rate on heat stress-mediated cell death. When protein synthesis was attenuated using cycloheximide or homoharringtonine, cell death due to heat stress was significantly reduced. In summation, we propose that transient modulation of protein synthesis by eIF2α phosphorylation has a pivotal role in protecting cells from heat stress-induced apoptosis. Therefore, pharmacological agents that promote eIF2α phosphorylation or reduce ER stress may contribute to the development of promising therapeutic approaches against heat-related diseases.

PERK-Mediated eIF2α Phosphorylation Contributes to The Protection of Dopaminergic Neurons from Chronic Heat Stress in Drosophila

“…It is generally accepted that decreased protein synthesis is critical to protect cells from stress [45,46]. Importantly, we showed that translational attenuation upon heat stress was crucial to protect cells [22]. Based on these results, we hypothesized that the attenuation of protein synthesis by PERK-mediated eIF2α phosphorylation might be required to protect neuronal cells against chronic heat stress in vivo.…”

“…We previously showed that heat exposure caused a disturbance in proteostasis not only in the cytosol but also in the ER, and it subsequently induced UPR signaling in mouse embryo fibroblasts (MEFs) [22]. Although several studies showed the hyperthermal effect on Drosophila and mice [30,31], there has been no research on how heat stress is correlated with ER stress in vivo.…”

“…It has been reported that eIF2α phosphorylation and subsequent attenuation of protein synthesis are critical in the protection of cells from heat-stress-mediated cellular dysfunction and/or death [22]. To further understand the significance of eIF2α phosphorylation under chronic hyperthermal conditions in Drosophila brain in an in vivo model, we analyzed the level of eIF2α phosphorylation in head extracts following chronic heat exposure.…”

“…Since high-temperature heat exposure causes protein aggregation and denaturation inside cells, it is likely that heat stress could lead to disturbed proteostasis in the ER [20,21]. We previously reported that heat exposure induces ER stress, and the PERK/eIF2α phosphorylation branch of the UPR is essential to protect cells from heat-stress-mediated apoptosis [22]. However, the precise role of ER stress and activation of the UPR signaling pathway by heat exposure in the pathogenesis of neurodegenerative disease has not been explored.…”

Selenium Attenuates Chronic Heat Stress-Induced Apoptosis via the Inhibition of Endoplasmic Reticulum Stress in Mouse Granulosa Cells

“…Furthermore, it is worth noting that most stress conditions, such as deficiency of growth factors, heat shock, and ER stress, also leads to disruption of the activity of the eIF2 initiating factor by phosphorylation of its α subunit. Phosphorylation eIF2α results in the formation of a stable eIF2-GDP complex with eIF2B, which strongly reduces the ability to exchange nucleotides guanine by eIF2B [53,54]. And it has been demonstrated that down-regulation of PERK-eIF2α-ATF4-CHOP pathway inhibits ER stress-mediated apoptosis [55].…”