Deciphering the roles of cystathionine gamma-lyase/H2S system in Fe-S protein biogenesis and iron homeostasis

硫化氢（H2S）传统上被认为是一种有毒气体，但最近被认为是一种无处不在的信号分子，它调节着许多不同物种（从微生物到动物再到人类）的各种生理过程。H2S可以由氨基酸半胱氨酸通过维生素b6依赖性酶半胱硫氨酸γ -裂解酶（CSE）内源性产生。H2S能够通过在活性半胱氨酸残基中产生氢过硫化物（-SSH）对蛋白质进行翻译后修饰，称为s -巯基化。Fe-S簇是许多蛋白质最古老的氧化还原中心，这些蛋白质参与了所有生命王国的能量产生、氧气运输、DNA复制和修复。另一种高度保守的维生素b6依赖性酶半胱氨酸脱硫酶（NFS1）可以分解半胱氨酸，用于铁-硫簇生物合成的第一步。鉴于CSE和NFS1具有许多相似的化学特征，并且H2S和铁在细胞功能的调节中相互依赖，因此研究哺乳动物细胞中H2S信号、铁代谢和Fe-S簇形成之间的相互关系是必不可少的。我的长期目标是阐明H2S的生物学重要性，以提高我们对多种细胞功能调控的理解，并更好地培养该领域的下一代研究人员。通过本研究项目，短期目标是确定不同应激条件下铁稳态和铁依赖性细胞死亡（铁死亡）中H2S代谢和Fe-S蛋白生物发生的相互作用。本项目提出了两个具体目标：1)研究CSE/H2S系统对NFS1功能和Fe-S簇生物合成及稳定性的调节；2)研究CSE/H2S系统在应激条件下（低氧和铁超载/剥夺）铁代谢和铁中毒敏感性中的作用。结合骨骼肌细胞和心脏细胞的遗传、生化、光谱和机制研究，该程序可能为理解哺乳动物细胞中H2S信号和Fe-S蛋白的生物发生提供新的范例。

Hydrogen sulfide (H2S) is traditionally known as a toxic gas but recently recognized as a ubiquitous signal molecule, which regulates a variety of physiological processes in many different species (from microbes to animals to human). H2S can be endogenously produced from the amino acid cysteine by a vitamin B6-dependent enzyme cystathionine gamma-lyase (CSE). H2S is capable of post-translational modification of proteins by yielding a hydropersulfide (-SSH) in the active cysteine residues, termed as S-sulfhydration. Fe-S clusters are the most ancient redox centers for numerous proteins involved in energy production, oxygen transport, DNA replication and repair in all kingdoms of life. Another highly conserved vitamin B6-dependent enzyme cysteine desulfurase (NFS1) can decompose cysteine for the very first step of Fe-S cluster biosynthesis. Given the facts that CSE and NFS1 share many similar chemical features and H2S and iron are mutually dependent in the regulation of cellular functions, it is indispensable to investigate the interconnections among H2S signals, iron metabolism, and Fe-S cluster formation in mammalian cells.         My long-term goal is to elucidate the biological importance of H2S in order to improve our understanding of the regulation of a multitude of cellular functions, and to better train the next generation of researchers in this field. The short-term goal, through this research program, is to determine the interaction of H2S metabolism and Fe-S protein biogenesis in iron homeostasis and iron-dependent cell death (ferroptosis) under various stress conditions.         Two specific objectives are proposed in this program: 1) investigate the regulation of CSE/H2S system on NFS1 functions and Fe-S cluster biosynthesis and stability; 2) examine the role of CSE/H2S system in iron metabolism and ferroptosis sensitivity under stress conditions (low oxygen and iron overload/deprivation). In combination with genetic, biochemical, spectroscopic, and mechanistic studies in both skeletal muscle cells and heart cells, this program may lead to new paradigms in the understanding of H2S signals and Fe-S protein biogenesis in mammalian cells.