Delaunay-Moisan Agnès, Ponsero Alise, Toledano Michel B
Institute for Integrative Biology of the Cell (I2BC), LSOC, SBIGEM, CEA, CNRS, Université Paris-Sud , Université Paris-Saclay, Gif-sur-Yvette, France .
Antioxid Redox Signal. 2017 Nov 20;27(15):1178-1199. doi: 10.1089/ars.2017.7148. Epub 2017 Sep 26.
Disturbance of glutathione (GSH) metabolism is a hallmark of numerous diseases, yet GSH functions are poorly understood. One key to this question is to consider its functional compartmentation. GSH is present in the endoplasmic reticulum (ER), where it competes with substrates for oxidation by the oxidative folding machinery, composed in eukaryotes of the thiol oxidase Ero1 and proteins from the disulfide isomerase family (protein disulfide isomerase). Yet, whether GSH is required for proper ER oxidative protein folding is a highly debated question. Recent Advances: Oxidative protein folding has been thoroughly dissected over the past decades, and its actors and their mode of action elucidated. Genetically encoded GSH probes have recently provided an access to subcellular redox metabolism, including the ER.
Of the few often-contradictory models of the role of GSH in the ER, the most popular suggest it serves as reducing power. Yet, as a reductant, GSH also activates Ero1, which questions how GSH can nevertheless support protein reduction. Hence, whether GSH operates in the ER as a reductant, an oxidant, or just as a "blank" compound mirroring ER/periplasm redox activity is a highly debated question, which is further stimulated by the puzzling occurrence of GSH in the Escherichia coli periplasmic "secretory" compartment, aside from the Dsb thiol-reducing and oxidase pathways.
Addressing the mechanisms controlling GSH traffic in and out of the ER/periplasm and its recycling will help address GSH function in secretion. In addition, as thioredoxin reductase was recently implicated in ER oxidative protein folding, the relative contribution of each of these two reducing pathways should now be addressed. Antioxid. Redox Signal. 27, 1178-1199.
谷胱甘肽（GSH）代谢紊乱是众多疾病的一个标志，但对GSH的功能了解甚少。解决这个问题的一个关键是考虑其功能区室化。GSH存在于内质网（ER）中，在那里它与底物竞争被氧化折叠机制氧化，在真核生物中，氧化折叠机制由硫醇氧化酶Ero1和二硫键异构酶家族的蛋白质（蛋白质二硫键异构酶）组成。然而，GSH对于内质网中正确的氧化蛋白折叠是否必需是一个备受争议的问题。最新进展：在过去几十年中，氧化蛋白折叠已被深入剖析，其作用因子及其作用方式也已阐明。最近，基因编码的GSH探针为研究亚细胞氧化还原代谢，包括内质网中的代谢，提供了途径。
在关于GSH在内质网中作用的少数几个常常相互矛盾的模型中，最流行的模型认为它作为还原力起作用。然而，作为一种还原剂，GSH也会激活Ero1，这就对GSH如何仍然能够支持蛋白质还原提出了疑问。因此，GSH在内质网中是作为还原剂、氧化剂起作用，还是仅仅作为反映内质网/周质氧化还原活性的“空白”化合物起作用，是一个备受争议的问题，除了Dsb硫醇还原和氧化酶途径外，大肠杆菌周质“分泌”区室中GSH的奇怪出现进一步激发了这个问题的讨论。
研究控制GSH进出内质网/周质及其循环利用的机制，将有助于阐明GSH在分泌过程中的功能。此外，由于最近发现硫氧还蛋白还原酶与内质网氧化蛋白折叠有关，现在应该研究这两种还原途径各自的相对贡献。《抗氧化与氧化还原信号》27卷，第1178 - 1199页 。
