The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

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.

Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling

“…It has been reported that NO may regulate the ER stress through modifications of its chaperon proteins [41] however, lacunae exist. Among numerous chaperon the protein disulfide isomerase is most studied [46]. Besides this, NO could also nitrosylate the ER membrane located sensors of ER stress (PERK1, IRE1 and ATF6) [47,48].…”

“…In AD pathology, the correlation of NO and PDI has well suggested through complexities of unfolded protein responses [49]. In 2019, the emerging role of various electrophiles including NO has also been suggested as regulator of ER stress in various diseases [46]. Oxidative stress is correlated with impairment of mitochondrial functions and thus afflicted cellular physiology which could lead to the activation of chaperons and may subsequently initiate the ER stress and decide the cellular fate.…”

Protein Lipoxidation: Basic Concepts and Emerging Roles

“…This can increase the exposure of hidden residues, rendering the protein more vulnerable to further modification [ 31 ]. As a result, the unfolded protein response (UPR) may be activated [ 67 , 68 , 69 , 70 ]. In addition, cross-linking or aggregation of proteins prevents their degradation via the 20S proteasome; inhibition of proteasome function may then occur, which directly affects cell viability and commonly results in cell death [ 71 , 72 ].…”

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

“…Recently, an emerging role of reactive electrophilic species (RES) as key regulators for the UPR, more specifically the IRE1 pathway, have been described [123]. Furthermore, RES have been reported to be involved in ER-stress related diseases, including neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), and cancer [124,125,126].…”