Cystine-dependent antiporters buffer against excess intracellular reactive sulfur species-induced stress.
Cystine-dependent antiporters buffer against excess intracellular reactive sulfur species-induced stress.
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DOI：
10.1016/j.redox.2022.102514
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发表时间：
2022-11
期刊：
影响因子：
11.4
通讯作者：
Kumagai, Yoshito
中科院分区：
文献类型：
--
作者：
Akiyama, Masahiro;Unoki, Takamitsu;Aoki, Hanako;Nishimura, Akiyuki;Shinkai, Yasuhiro;Warabi, Eiji;Nishiyama, Kazuhiro;Furumoto, Yuka;Anzai, Naohiko;Akaike, Takaaki;Nishida, Motohiro;Kumagai, Yoshito
活性硫物质（RSS）在氧化还原稳态中发挥作用;然而，对过量细胞内RSS的适应性细胞反应还不清楚。因此，在这项研究中，我们产生了转基因（Tg）小鼠过表达胱硫醚γ-裂解酶（CSE）产生过量的RSS。与预期相反，野生型和CSE Tg小鼠中RSS（如过硫化半胱氨酸（CysSSH））的组织浓度相当，但CSE Tg小鼠中CysSSH的血浆浓度显著高于野生型小鼠。在CSE Tg小鼠的原代肝细胞中也观察到这种过剩细胞内RSS的输出。原代肝细胞暴露于RSS发生器四硫化钠（Na 2S 4）导致RSS的细胞内浓度最初增加，随后在输出到细胞外空间后恢复到基础水平。有趣的是，在所有氨基酸中，胱氨酸（CysSSCys）被发现是必不可少的CysSSH输出从原代小鼠肝细胞，HepG 2细胞，和HEK 293细胞在Na 2S 4暴露，表明胱氨酸/谷氨酸转运蛋白（SLC 7A 11）的贡献，至少部分，CysSSH输出。我们建立了SLC 7A 11基因敲除和过表达的HepG 2细胞系，并用它们来证实SLC 7A 11是CysSSCys和CysSSH的主要反向转运蛋白。我们观察到，过量CysSSH从细胞中的流出不良增强了由Na 2S 4暴露诱导的细胞应激，如细胞内蛋白的多硫化、线粒体损伤和细胞毒性。这些结果表明，过量的细胞内RSS的细胞反应的存在下，涉及过量的CysSSH的细胞外流出的胱氨酸依赖性转运蛋白，以维持细胞内的氧化还原稳态。
Reactive sulfur species (RSS) play a role in redox homeostasis; however, adaptive cell responses to excessive intracellular RSS are not well understood. Therefore, in this study, we generated transgenic (Tg) mice overexpressing cystathionine gamma-lyase (CSE) to produce excessive RSS. Contrary to expectations, tissue concentrations of RSS, such as cysteine persulfide (CysSSH), were comparable in both wild-type and CSE Tg mice, but the plasma concentrations of CysSSH were significantly higher in CSE Tg mice than in wild-type mice. This export of surplus intracellular RSS was also observed in primary hepatocytes of CSE Tg mice. Exposure of primary hepatocytes to the RSS generator sodium tetrasulfide (Na2S4) resulted in an initial increase in the intracellular concentration of RSS, which later returned to basal levels after export into the extracellular space. Interestingly, among all amino acids, cystine (CysSSCys) was found to be essential for CysSSH export from primary mouse hepatocytes, HepG2 cells, and HEK293 cells during Na2S4 exposure, suggesting that the cystine/glutamate transporter (SLC7A11) contributes, at least partially, to CysSSH export. We established HepG2 cell lines with knockout and overexpression of SLC7A11 and used them to confirm SLC7A11 as the predominant antiporter of CysSSCys and CysSSH. We observed that the poor efflux of excess CysSSH from the cell enhanced cellular stresses induced by Na2S4 exposure, such as polysulfidation of intracellular proteins, mitochondrial damage, and cytotoxicity. These results suggest the presence of a cellular response to excess intracellular RSS that involves the extracellular efflux of excess CysSSH by a cystine-dependent transporter to maintain intracellular redox homeostasis.
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影响因子：
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影响因子：
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