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普遍存在的信号分子，它调节许多不同物种（从微生物到动物再到人类）的各种生理过程。H2S可以通过维生素B6依赖性酶胱硫醚γ-裂解酶（CSE）从氨基酸半胱氨酸内源性产生。H2S能够通过在活性半胱氨酸残基中产生氢过硫化物（-SSH）而对蛋白质进行翻译后修饰，称为S-硫氢化。Fe-S团簇是最古老的氧化还原中心，许多蛋白质参与能量生产，氧气运输，DNA复制和修复，在所有生命王国中。另一种高度保守的维生素B6依赖性酶半胱氨酸脱硫酶（NFS 1）可以分解半胱氨酸作为Fe-S簇生物合成的第一步。鉴于CSE和NFS 1具有许多相似的化学特征，H2S和铁在细胞功能调节中相互依赖，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节的理解，并更好地培养该领域的下一代研究人员。短期目标，通过这项研究计划，是确定在铁稳态和铁依赖性细胞死亡（ferroptosis）在各种应激条件下的H2S代谢和Fe-S蛋白生物合成的相互作用。 本研究的主要目的是：1）研究CSE/H2S系统对NFS 1功能和Fe-S簇生物合成及稳定性的调控作用; 2）研究CSE/H2S系统在低氧和缺铁胁迫条件下对铁代谢和铁凋亡敏感性的影响。结合骨骼肌细胞和心脏细胞的遗传，生化，光谱和机制研究，该计划可能会导致在哺乳动物细胞中的H2S信号和Fe-S蛋白生物合成的理解新的范例。

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.