PDF(Pubmed)
Abstract：
Dedicated genetic pathways regulate cysteine homeostasis. For example, high levels of cysteine activate cysteine dioxygenase, a key enzyme in cysteine catabolism in most animal and many fungal species. The mechanism by which cysteine dioxygenase is regulated is largely unknown. In an unbiased genetic screen for mutations that activate cysteine dioxygenase (cdo-1) in the nematode Caenorhabditis elegans, we isolated loss-of-function mutations in rhy-1 and egl-9, which encode proteins that negatively regulate the stability or activity of the oxygen-sensing hypoxia inducible transcription factor (hif-1). EGL-9 and HIF-1 are core members of the conserved eukaryotic hypoxia response. However, we demonstrate that the mechanism of HIF-1-mediated induction of cdo-1 is largely independent of EGL-9 prolyl hydroxylase activity and the von Hippel-Lindau E3 ubiquitin ligase, the classical hypoxia signaling pathway components. We demonstrate that C. elegans cdo-1 is transcriptionally activated by high levels of cysteine and hif-1. hif-1-dependent activation of cdo-1 occurs downstream of an H2S-sensing pathway that includes rhy-1, cysl-1, and egl-9. cdo-1 transcription is primarily activated in the hypodermis where it is also sufficient to drive sulfur amino acid metabolism. Thus, the regulation of cdo-1 by hif-1 reveals a negative feedback loop that maintains cysteine homeostasis. High levels of cysteine stimulate the production of an H2S signal. H2S then acts through the rhy-1/cysl-1/egl-9 signaling pathway to increase HIF-1-mediated transcription of cdo-1, promoting degradation of cysteine via CDO-1.
Proteins are large molecules in our cells that perform various roles, from acting as channels through which nutrients can enter the cell, to forming structural assemblies that help the cell keep its shape. Proteins are formed of chains of building blocks called amino acids. There are 20 common amino acids, each with a different ‘side chain’ that confers it with specific features. Cysteine is one of these 20 amino acids. Its side chain has a ‘thiol’ group, made up of a sulfur atom and a hydrogen atom. This thiol group is very reactive, and it is an essential building block of enzymes (proteins that speed up chemical reactions within the cell), structural proteins and signaling molecules. While cysteine is an essential amino acid for the cell to function, excess cysteine can be toxic. The concentration of cysteine in animal cells is tightly regulated by an enzyme called cysteine dioxygenase. This enzyme is implicated in two rare conditions that affect metabolism, where the product of cysteine dioxygenase is a key driver of disease severity. Additionally, cysteine dioxygenase acts as a tumor suppressor gene, and its activity becomes blocked in diverse cancers. Understanding how cysteine dioxygenase is regulated may be important for research into these conditions. While it has been shown that excess cysteine drives the production and activity of cysteine dioxygenase, how the cell detects high levels of cysteine remained unknown. Warnhoff et al. sought to resolve this question using the roundworm Caenorhabditis elegans. First, the scientists demonstrated that, like in mammals, high levels of cysteine drive the production of cysteine dioxygenase in C. elegans. Next, the researchers used an approach called an unbiased genetic screening to find genes that induce cysteine dioxygenase production when they are mutated. These experiments revealed that the protein HIF-1 can drive the production of cysteine dioxygenase when it is activated by a pathway that senses hydrogen sulfide gas. Based on these results, Warnhoff et al. propose that high levels of cysteine lead to the production of hydrogen sulfide gas that in turn drives the production of cysteine dioxygenase via HIF-1 activation of gene expression. The results reported by Warnhoff et al. suggest that modulating HIF-1 signaling could control the activity of cysteine dioxygenase. This information could be used in the future to develop therapies for molybdenum cofactor deficiency, isolated sulfite oxidase deficiency and several types of cancer. However, first it will be necessary to demonstrate that the same signaling pathway is active in humans.
Proteins are large molecules in our cells that perform various roles, from acting as channels through which nutrients can enter the cell, to forming structural assemblies that help the cell keep its shape. Proteins are formed of chains of building blocks called amino acids. There are 20 common amino acids, each with a different ‘side chain’ that confers it with specific features. Cysteine is one of these 20 amino acids. Its side chain has a ‘thiol’ group, made up of a sulfur atom and a hydrogen atom. This thiol group is very reactive, and it is an essential building block of enzymes (proteins that speed up chemical reactions within the cell), structural proteins and signaling molecules. While cysteine is an essential amino acid for the cell to function, excess cysteine can be toxic. The concentration of cysteine in animal cells is tightly regulated by an enzyme called cysteine dioxygenase. This enzyme is implicated in two rare conditions that affect metabolism, where the product of cysteine dioxygenase is a key driver of disease severity. Additionally, cysteine dioxygenase acts as a tumor suppressor gene, and its activity becomes blocked in diverse cancers. Understanding how cysteine dioxygenase is regulated may be important for research into these conditions. While it has been shown that excess cysteine drives the production and activity of cysteine dioxygenase, how the cell detects high levels of cysteine remained unknown. Warnhoff et al. sought to resolve this question using the roundworm Caenorhabditis elegans. First, the scientists demonstrated that, like in mammals, high levels of cysteine drive the production of cysteine dioxygenase in C. elegans. Next, the researchers used an approach called an unbiased genetic screening to find genes that induce cysteine dioxygenase production when they are mutated. These experiments revealed that the protein HIF-1 can drive the production of cysteine dioxygenase when it is activated by a pathway that senses hydrogen sulfide gas. Based on these results, Warnhoff et al. propose that high levels of cysteine lead to the production of hydrogen sulfide gas that in turn drives the production of cysteine dioxygenase via HIF-1 activation of gene expression. The results reported by Warnhoff et al. suggest that modulating HIF-1 signaling could control the activity of cysteine dioxygenase. This information could be used in the future to develop therapies for molybdenum cofactor deficiency, isolated sulfite oxidase deficiency and several types of cancer. However, first it will be necessary to demonstrate that the same signaling pathway is active in humans.
摘要：
专用遗传途径调节半胱氨酸稳态。例如,高水平的半胱氨酸激活半胱氨酸双加氧酶，在大多数动物和许多真菌物种中，半胱氨酸分解代谢的关键酶。半胱氨酸双加氧酶的调节机制在很大程度上是未知的。在线虫秀丽隐杆线虫中激活半胱氨酸双加氧酶（cdo-1）的突变的无偏遗传筛选中，我们分离了rhy-1和egl-9中的功能缺失突变，它们编码负调节氧敏感缺氧诱导转录因子（hif-1）稳定性或活性的蛋白质。EGL-9和HIF-1是保守的真核低氧反应的核心成员。然而,我们证明了HIF-1介导的cdo-1诱导的机制在很大程度上独立于EGL-9脯氨酸羟化酶活性和vonHippel-LindauE3泛素连接酶,经典的缺氧信号通路成分。我们证明秀丽隐杆线虫cdo-1被高水平的半胱氨酸和hif-1转录激活。cdo-1的hif-1依赖性激活发生在H2S传感途径的下游，该途径包括rhy-1，cysl-1和egl-9。cdo-1转录主要在皮下组织中被激活，在那里它也足以驱动硫氨基酸代谢。因此，hif-1对cdo-1的调节揭示了一个维持半胱氨酸稳态的负反馈回路。高水平的半胱氨酸刺激H2S信号的产生。然后,H2S通过rhy-1/cysl-1/egl-9信号传导途径起作用以增加HIF-1介导的cdo-1转录,促进半胱氨酸经由CDO-1的降解。
蛋白质是细胞中的大分子，发挥各种作用，作为营养物质进入细胞的通道，形成帮助细胞保持其形状的结构组件。蛋白质由称为氨基酸的结构单元链形成。有20种常见的氨基酸，每个都有一个不同的“侧链”，赋予它特定的特征。半胱氨酸是这20种氨基酸之一。它的侧链有一个“硫醇”基团，由硫原子和氢原子组成.这个巯基是非常活泼的,它是酶（加速细胞内化学反应的蛋白质）的基本组成部分，结构蛋白和信号分子。虽然半胱氨酸是细胞发挥作用的必需氨基酸，过量的半胱氨酸可能是有毒的。动物细胞中半胱氨酸的浓度受到称为半胱氨酸双加氧酶的酶的严格调节。这种酶与两种影响新陈代谢的罕见条件有关，其中半胱氨酸双加氧酶的产物是疾病严重程度的关键驱动因素。此外,半胱氨酸双加氧酶作为抑癌基因，它的活性在各种癌症中被阻断。了解半胱氨酸双加氧酶如何调节对于研究这些条件可能很重要。虽然已经表明过量的半胱氨酸驱动半胱氨酸双加氧酶的产生和活性,细胞如何检测高水平的半胱氨酸仍然未知。Warnhoff等人。试图解决这个问题，使用蛔虫秀丽隐杆线虫。首先,科学家证明，就像哺乳动物一样，高水平的半胱氨酸驱动线虫中半胱氨酸双加氧酶的产生。接下来,研究人员使用一种称为无偏基因筛选的方法来寻找突变时诱导半胱氨酸双加氧酶产生的基因。这些实验表明，蛋白质HIF-1在通过感测硫化氢气体的途径激活时可以驱动半胱氨酸双加氧酶的产生。基于这些结果,Warnhoff等人。认为高水平的半胱氨酸导致硫化氢气体的产生,而硫化氢气体又通过HIF-1激活基因表达来驱动半胱氨酸双加氧酶的产生。Warnhoff等人报道的结果。提示调节HIF-1信号可以控制半胱氨酸双加氧酶的活性。这些信息将来可以用于开发钼辅因子缺乏症的疗法，分离的亚硫酸盐氧化酶缺乏症和几种类型的癌症。然而,首先，有必要证明相同的信号通路在人类中是活跃的。
蛋白质是细胞中的大分子，发挥各种作用，作为营养物质进入细胞的通道，形成帮助细胞保持其形状的结构组件。蛋白质由称为氨基酸的结构单元链形成。有20种常见的氨基酸，每个都有一个不同的“侧链”，赋予它特定的特征。半胱氨酸是这20种氨基酸之一。它的侧链有一个“硫醇”基团，由硫原子和氢原子组成.这个巯基是非常活泼的,它是酶（加速细胞内化学反应的蛋白质）的基本组成部分，结构蛋白和信号分子。虽然半胱氨酸是细胞发挥作用的必需氨基酸，过量的半胱氨酸可能是有毒的。动物细胞中半胱氨酸的浓度受到称为半胱氨酸双加氧酶的酶的严格调节。这种酶与两种影响新陈代谢的罕见条件有关，其中半胱氨酸双加氧酶的产物是疾病严重程度的关键驱动因素。此外,半胱氨酸双加氧酶作为抑癌基因，它的活性在各种癌症中被阻断。了解半胱氨酸双加氧酶如何调节对于研究这些条件可能很重要。虽然已经表明过量的半胱氨酸驱动半胱氨酸双加氧酶的产生和活性,细胞如何检测高水平的半胱氨酸仍然未知。Warnhoff等人。试图解决这个问题，使用蛔虫秀丽隐杆线虫。首先,科学家证明，就像哺乳动物一样，高水平的半胱氨酸驱动线虫中半胱氨酸双加氧酶的产生。接下来,研究人员使用一种称为无偏基因筛选的方法来寻找突变时诱导半胱氨酸双加氧酶产生的基因。这些实验表明，蛋白质HIF-1在通过感测硫化氢气体的途径激活时可以驱动半胱氨酸双加氧酶的产生。基于这些结果,Warnhoff等人。认为高水平的半胱氨酸导致硫化氢气体的产生,而硫化氢气体又通过HIF-1激活基因表达来驱动半胱氨酸双加氧酶的产生。Warnhoff等人报道的结果。提示调节HIF-1信号可以控制半胱氨酸双加氧酶的活性。这些信息将来可以用于开发钼辅因子缺乏症的疗法，分离的亚硫酸盐氧化酶缺乏症和几种类型的癌症。然而,首先，有必要证明相同的信号通路在人类中是活跃的。
