Polysulfide and Persulfide-mediated Activation of the PERK-eIF2α-ATF4 Pathway Increases Sestrin2 Expression and Reduces Methylglyoxal Toxicity

Overview

Journal Redox Biol

Specialties Biology
Cell Biology
Endocrinology

Date 2024 Dec 12

PMID 39667306

Authors

Shin Koike

Hideo Kimura

Yuki Ogasawara

Affiliations

Soon will be listed here.

Abstract

Unfolded protein response (UPR) is activated in cells under endoplasmic reticulum (ER) stress. One sensor protein involved in this response is PERK, which is activated through its redox-dependent oligomerization. Prolonged UPR activation is associated with the development and progression of various diseases, making it essential to understanding the redox regulation of PERK. Sulfane sulfur, such as polysulfides and persulfides, can modify the cysteine residues and regulate the function of various proteins. However, the regulatory mechanism and physiological effects of sulfane sulfur on the PERK-eIF2α-ATF4 pathway remain poorly understood. This study focuses on the persulfidation of PERK to elucidate the effects of polysulfides on the PERK-eIF2α-ATF4 pathway and investigate its cytoprotective mechanism. Here, we demonstrated that polysulfide treatment promoted the oligomerization of PERK and PTP1B in neuronal cells using western blotting under nonreducing conditions. We also observed that l-cysteine, a biological source of sulfane sulfur, promoted the oligomerization of PERK and the knockdown of CBS and 3-MST, two sulfane sulfur-producing enzymes, and reduced PERK oligomerization induced by l-cysteine treatment. Furthermore, the band shift assay and LC-MS/MS studies revealed that polysulfides and persulfides induce PTP1B and PERK persulfidation. Additionally, polysulfides promoted eIF2α phosphorylation and ATF4 accumulation in the nucleus, suggesting that polysulfides activate the PERK-eIF2α-ATF4 pathway in neuronal cells. Moreover, polysulfides protected neuronal cells from methylglyoxal-induced toxicity, and this protective effect was reduced when the expression of Sestrin2, regulated by ATF4 activity, was suppressed. This study identified a novel mechanism for the activation of the PERK-eIF2α-ATF4 pathway through persulfidation by polysulfides and persulfides. Interestingly, activation of this pathway overcame the toxicity of methylglyoxal in dependence on Sestrin2 expression. These findings deepen our understanding of neuronal diseases involving ER stress and UPR disturbance and may inspire new therapeutic strategies.

References

Rabbani N, Thornalley P . Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples. Nat Protoc. 2014; 9(8):1969-79. DOI: 10.1038/nprot.2014.129. View

Akaike T, Morita M, Ogata S, Yoshitake J, Jung M, Sekine H . New aspects of redox signaling mediated by supersulfides in health and disease. Free Radic Biol Med. 2024; 222:539-551. DOI: 10.1016/j.freeradbiomed.2024.07.007. View

Hirayama C, Machida K, Noi K, Murakawa T, Okumura M, Ogura T . Distinct roles and actions of protein disulfide isomerase family enzymes in catalysis of nascent-chain disulfide bond formation. iScience. 2021; 24(4):102296. PMC: 8024706. DOI: 10.1016/j.isci.2021.102296. View

Harding H, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M . Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000; 6(5):1099-108. DOI: 10.1016/s1097-2765(00)00108-8. View

Eletto D, Chevet E, Argon Y, Appenzeller-Herzog C . Redox controls UPR to control redox. J Cell Sci. 2014; 127(Pt 17):3649-58. DOI: 10.1242/jcs.153643. View

Angeloni C, Zambonin L, Hrelia S . Role of methylglyoxal in Alzheimer's disease. Biomed Res Int. 2014; 2014:238485. PMC: 3966409. DOI: 10.1155/2014/238485. View

Koike S, Ogasawara Y . Sulfur Atom in its Bound State Is a Unique Element Involved in Physiological Functions in Mammals. Molecules. 2016; 21(12). PMC: 6273515. DOI: 10.3390/molecules21121753. View

Zhong H, Yu H, Chen J, Sun J, Guo L, Huang P . Hydrogen Sulfide and Endoplasmic Reticulum Stress: A Potential Therapeutic Target for Central Nervous System Degeneration Diseases. Front Pharmacol. 2020; 11:702. PMC: 7240010. DOI: 10.3389/fphar.2020.00702. View

Harding H, Zhang Y, Ron D . Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999; 397(6716):271-4. DOI: 10.1038/16729. View

10.

Schilling D, Ditroi T, Barayeu U, Juranyi E, Nagy P, Dick T . The influence of alkylating agents on sulfur-sulfur bonds in per- and polysulfides. Curr Opin Chem Biol. 2023; 76:102368. DOI: 10.1016/j.cbpa.2023.102368. View

11.

Bettaieb A, Liu S, Xi Y, Nagata N, Matsuo K, Matsuo I . Differential regulation of endoplasmic reticulum stress by protein tyrosine phosphatase 1B and T cell protein tyrosine phosphatase. J Biol Chem. 2011; 286(11):9225-35. PMC: 3059022. DOI: 10.1074/jbc.M110.186148. View

12.

Kimura Y, Toyofuku Y, Koike S, Shibuya N, Nagahara N, Lefer D . Identification of H2S3 and H2S produced by 3-mercaptopyruvate sulfurtransferase in the brain. Sci Rep. 2015; 5:14774. PMC: 4594004. DOI: 10.1038/srep14774. View

13.

Iwawaki T, Akai R, Toyoshima T, Takeda N, Ishikawa T, Yamamura K . Transgenic mouse model for imaging of ATF4 translational activation-related cellular stress responses in vivo. Sci Rep. 2017; 7:46230. PMC: 5384252. DOI: 10.1038/srep46230. View

14.

Koike S, Kayama T, Yamamoto S, Komine D, Tanaka R, Nishimoto S . Polysulfides protect SH-SY5Y cells from methylglyoxal-induced toxicity by suppressing protein carbonylation: A possible physiological scavenger for carbonyl stress in the brain. Neurotoxicology. 2016; 55:13-19. DOI: 10.1016/j.neuro.2016.05.003. View

15.

Jeong S, Lee K . Methylglyoxal-Derived Advanced Glycation End Product (AGE4)-Induced Apoptosis Leads to Mitochondrial Dysfunction and Endoplasmic Reticulum Stress through the RAGE/JNK Pathway in Kidney Cells. Int J Mol Sci. 2021; 22(12). PMC: 8235496. DOI: 10.3390/ijms22126530. View

16.

Hetz C . The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012; 13(2):89-102. DOI: 10.1038/nrm3270. View

17.

Abe K, Kimura H . The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 1996; 16(3):1066-71. PMC: 6578817. View

18.

Krishnan N, Fu C, Pappin D, Tonks N . H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci Signal. 2011; 4(203):ra86. PMC: 3328411. DOI: 10.1126/scisignal.2002329. View

19.

Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J . Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol. 1999; 1(8):479-85. DOI: 10.1038/70265. View

20.

Akaike T, Ida T, Wei F, Nishida M, Kumagai Y, Alam M . Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. Nat Commun. 2017; 8(1):1177. PMC: 5660078. DOI: 10.1038/s41467-017-01311-y. View