Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway.
Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway.
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DOI：
10.1042/bst20150021
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发表时间：
2015-08
影响因子：
3.9
通讯作者：
Schmidt EE
中科院分区：
文献类型：
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作者：
Schmidt EE
NADPH将还原力从生物能途径转移到硫氧还蛋白还原酶-1（TrxR 1）和谷胱甘肽还原酶（GR），以支持基本的还原系统。令人惊讶的是，最近显示缺乏TrxR 1和GR（“TR/GR-空”）的小鼠肝脏可以使用先前未被认识到的由膳食甲硫氨酸提供的还原力的NADPH非依赖性来源来维持氧化还原（还原-氧化）体内平衡。NADPH依赖性系统在肝脏中是稳健冗余的，因此单独破坏TrxR 1或GR不会引起氧化应激。然而，TrxR 1的破坏诱导转录因子Nrf 2（核因子红细胞衍生的2-样-2），而GR的破坏不会。这表明Nrf 2通路直接响应于硫氧还蛋白-1（Trx 1）系统的状态。Nrf 2的近端调节因子是Keap 1（Kelch样ECH相关蛋白-1），一种富含半胱氨酸（Cys）的蛋白质，通常与Nrf 2短暂相互作用，靶向其降解。在氧化应激过程中，这种相互作用是稳定的，防止新合成的Nrf 2降解，从而允许Nrf 2积累。在Trx 1系统中，TrxR 1和过氧化物酶（Prxs）含有细胞中一些最具反应性的亲核残基，使它们成为氧化剂或亲电试剂的目标。我们建议，Keap 1的活性，因此NRF 2的调节Trx 1系统酶与氧化剂的相互作用。在TR/GR缺失的肝脏中，Nrf 2活性被进一步诱导，揭示了TrxR非依赖性系统也抑制Nrf 2，这些可能是由更极端的挑战诱导的。
NADPH transfers reducing power from bioenergetic pathways to thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR) to support essential reductive systems. Surprisingly, it was recently shown that mouse livers lacking both TrxR1 and GR (‘TR/GR-null’) can sustain redox (reduction-oxidation) homoeostasis using a previously unrecognized NADPH-independent source of reducing power fuelled by dietary methionine. The NADPH-dependent systems are robustly redundant in liver, such that disruption of either TrxR1 or GR alone does not cause oxidative stress. However, disruption of TrxR1 induces transcription factor Nrf2 (nuclear factor erythroid-derived 2-like-2) whereas disruption of GR does not. This suggests the Nrf2 pathway responds directly to the status of the thioredoxin-1 (Trx1) system. The proximal regulator of Nrf2 is Keap1 (Kelch-like ECH-associated protein-1), a cysteine (Cys)-rich protein that normally interacts transiently with Nrf2, targeting it for degradation. During oxidative stress, this interaction is stabilized, preventing degradation of newly synthesized Nrf2, thereby allowing Nrf2 accumulation. Within the Trx1 system, TrxR1 and peroxiredoxins (Prxs) contain some of the most reactive nucleophilic residues in the cell, making them likely targets for oxidants or electrophiles. We propose that Keap1 activity and therefore Nrf2 is regulated by interactions of Trx1 system enzymes with oxidants. In TR/GR-null livers, Nrf2 activity is further induced, revealing that TrxR-independent systems also repress Nrf2 and these might be induced by more extreme challenges.