Abstract
The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.
Highlights
The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress
Further demonstration of the correlation between protein modification by HNE and disease is required, HNE might be useful as a biological marker to predict or diagnose disease given the association between high HNE concentration and pathological conditions
This theory is supported by another research group, which found that Trolox, a known reactive oxygen species (ROS) scavenger, inhibits MeHg-induced ER stress [116]
Summary
NO is a gaseous molecule with a short half-life that can pass through the plasma membrane to regulate various cellular responses, such as apoptosis, proliferation, and neurotransmission [11,12,13,14,15,16,17]. A target cysteine of S-nitrosylation has been suggested to be the thiolate anion, which is located at the acid–base motif [28,29] This modification changes the enzyme activity, stability, or localization of target proteins [30]. Rotenone-induced iNOS expression increases SNO-PDI formation, subsequently leading to apoptotic cell death. The SOD1 G93A mutant protein, representing a type of familial ALS gene mutation, aggregated and accumulated via SNO-PDI activity [62,63]. These results indicate that nitrosative stress induces ER stress mediated by SNO-PDI and, neuronal cell death
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