Levonen Anna-Liisa, Hill Bradford G, Kansanen Emilia, Zhang Jianhua, Darley-Usmar Victor M
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
Diabetes and Obesity Center, Institute of Molecular Cardiology, and Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, USA; Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA.
Free Radic Biol Med. 2014 Jun;71:196-207. doi: 10.1016/j.freeradbiomed.2014.03.025. Epub 2014 Mar 26.
Redox networks in the cell integrate signaling pathways that control metabolism, energetics, cell survival, and death. The physiological second messengers that modulate these pathways include nitric oxide, hydrogen peroxide, and electrophiles. Electrophiles are produced in the cell via both enzymatic and nonenzymatic lipid peroxidation and are also relatively abundant constituents of the diet. These compounds bind covalently to families of cysteine-containing, redox-sensing proteins that constitute the electrophile-responsive proteome, the subproteomes of which are found in localized intracellular domains. These include those proteins controlling responses to oxidative stress in the cytosol-notably the Keap1-Nrf2 pathway, the autophagy-lysosomal pathway, and proteins in other compartments including mitochondria and endoplasmic reticulum. The signaling pathways through which electrophiles function have unique characteristics that could be exploited for novel therapeutic interventions; however, development of such therapeutic strategies has been challenging due to a lack of basic understanding of the mechanisms controlling this form of redox signaling. In this review, we discuss current knowledge of the basic mechanisms of thiol-electrophile signaling and its potential impact on the translation of this important field of redox biology to the clinic. Emerging understanding of thiol-electrophile interactions and redox signaling suggests replacement of the oxidative stress hypothesis with a new redox biology paradigm, which provides an exciting and influential framework for guiding translational research.
细胞中的氧化还原网络整合了控制代谢、能量学、细胞存活和死亡的信号通路。调节这些通路的生理性第二信使包括一氧化氮、过氧化氢和亲电试剂。亲电试剂在细胞内通过酶促和非酶促脂质过氧化作用产生，也是饮食中相对丰富的成分。这些化合物与构成亲电试剂反应性蛋白质组的含半胱氨酸氧化还原感应蛋白家族共价结合，其亚蛋白质组存在于局部细胞内区域。这些包括那些控制细胞质中氧化应激反应的蛋白质——特别是Keap1-Nrf2通路、自噬-溶酶体通路以及包括线粒体和内质网在内的其他区室中的蛋白质。亲电试剂发挥作用的信号通路具有独特的特征，可用于新型治疗干预；然而，由于对控制这种氧化还原信号形式的机制缺乏基本了解，此类治疗策略的开发一直具有挑战性。在本综述中，我们讨论了目前关于硫醇-亲电试剂信号传导基本机制的知识及其对将这一氧化还原生物学重要领域转化为临床应用的潜在影响。对硫醇-亲电试剂相互作用和氧化还原信号传导的新认识表明，用新的氧化还原生物学范式取代氧化应激假说，这为指导转化研究提供了一个令人兴奋且有影响力的框架。
