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

解读胱硫醚γ-裂解酶/H2S系统在Fe-S蛋白生物发生和铁稳态中的作用

• 批准号: RGPIN-2022-05369
• 负责人: Yang, Guangdong
• 金额: $ 2.91万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748506
• 关键词: Deciphering; roles; cystathionine; gamma; lyase

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.

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。半胱氨酸可以通过依赖维生素B6的酶-胱硫醚-伽马裂解酶(CSE)在体内产生H_2S。硫化氢能够通过在活性半胱氨酸残基上产生一个过硫化物(-SSH)来对蛋白质进行翻译后修饰，称为S水合作用。铁-S簇是最古老的氧化还原中心，大量蛋白质参与能量生产、氧运输、DNA复制和修复，在所有生命王国。另一种高度保守的维生素B6依赖的半胱氨酸脱硫酶(Nfs1)可以分解半胱氨酸，是铁-S簇生物合成的第一步。鉴于CSE和NFS1有许多相似的化学特征，而且硫化氢和铁在细胞功能的调节中相互依赖，因此有必要研究哺乳动物细胞中硫化氢信号、铁代谢和铁-S簇形成之间的相互联系。他说，我的长期目标是阐明硫化氢的生物学重要性，以便提高我们对多种细胞功能调节的理解，并更好地培养这一领域的下一代研究人员。通过这一研究计划，短期目标是确定不同胁迫条件下硫化氢代谢和铁-S蛋白生物发生在铁稳态和铁依赖性细胞死亡(铁下垂)中的相互作用。本计划提出了两个具体目标：1)研究CSE/H_2S系统对NFS1功能和铁-S簇生物合成和稳定性的调节；2)研究CSE/H_2S系统在胁迫条件(低氧和铁过载/剥夺)下对铁代谢和铁下垂敏感性的作用。结合对骨骼肌细胞和心肌细胞的遗传、生化、光谱和机制研究，该计划可能导致理解哺乳动物细胞中的硫化氢信号和铁-S蛋白生物发生的新范式。