Stress resistance and the essential iron-sulphur cluster protein Rli1

生命的一个固有特征是有机体必须应对各种形式的环境压力。对于生活在有氧环境中的好氧生物，例如人类，氧气本身就是一种压力，因为它是活性氧物种(ROS)的来源。ROS对细胞的主要成分具有很强的破坏性。细胞中对ROS最敏感的分子是某些蛋白质的成分，称为铁-硫簇(FeS)。由于它们对氧的敏感性，这些FeS团簇被认为是成功有氧存在的主要限制因素。然而，FeS簇是必不可少的，而这种必要性似乎取决于生物体对FeS蛋白Rli1p的要求。Rli1p对生物体来说是必不可少的，因为它是蛋白质合成过程中所必需的。通过进化，Rli1p一直是生物学中最保守的蛋白质之一，这可能不是巧合。这种保守是有帮助的，因为它意味着可以在相对简单的模式生物中探索Rli1p的功能，比如酵母，这种模式生物很容易在实验室中培养，也很容易操纵进行实验。方便的是，酵母也被证明是研究细胞应激反应的理想模型，近年来产生了一系列与人类疾病过程和微生物生物技术应用相关的关键见解。通过酵母模型，我们最近发现了一种新的细胞功能，它有助于在应激状态下保持FES簇的完整性。这项工作为生物体如何应对有氧生活方式提供了新的见解。此外，在相关实验中，我们首次获得了Rli1p是决定细胞抗应激能力的关键因素的实验证据。这项研究方案以这一令人兴奋的发现为中心，得到了我们的初步数据的支持。具体地说，我们将测试这样的假设，即它的FES簇使Rli1p成为许多主要应激源的靶点，并且Rli1p的本质意味着这种靶向是应激期间细胞死亡的原因。工作方案将涉及筛选方法和具体操作，以检验这一假设。我们将研究在广泛的应力条件下的Rli1p函数。我们还将利用酵母遗传学的力量来确定在应激过程中影响Rli1p功能的细胞因素。此外，我们还将阐明Rli1p靶向的机制(S)。这些研究很重要，因为Rli1p以前没有在这种背景下被研究过，但我们讨论的证据表明，Rli1p很可能在决定生物体应对某些压力的能力方面发挥重要作用。如果这项研究可能被用于改善未来的生物技术过程或健康，阐明这一作用是至关重要的。

An inherent feature of life is that organisms must cope with various forms of environmental stress. For aerobic organisms which live in an oxygenated environment, e.g. humans, oxygen itself imposes a stress as it is the source of reactive oxygen species (ROS). ROS are highly damaging to the major components of cells. Among the most ROS-sensitive molecules of cells are components of certain proteins, termed iron-sulphur (FeS) clusters. Because of their oxygen sensitivity, these FeS clusters are considered a major limitation for successful aerobic existence. Nevertheless FeS clusters are essential, and that essentiality appears to rest on the requirement organisms have for the FeS protein Rli1p. Rli1p is essential to organisms because it is required for the process of protein synthesis. It may be no coincidence that, through evolution, Rli1p has been one of the most highly conserved proteins in biology. This conservation is helpful because it means that Rli1p function can be explored in relatively simple model organisms like yeast, which is very easy to grow in the lab and to manipulate for experiments. Conveniently, yeast has also proven an ideal model for studies of stress responses in cells, having yielded a range of key insights over recent years relevant to disease processes in humans and to the biotechnological applications of microorganisms. With the yeast model, we recently discovered a novel cellular function that helps to preserve the integrity of FeS clusters during stress. That work gave new insight to how organisms cope with an aerobic lifestyle. Moreover, in related experiments, we obtained the first experimental evidence that Rli1p is a key factor determining the stress resistance of cells. This research proposal is centered on that exciting discovery, supported by our preliminary data. Specifically, we will test the hypothesis that its FeS clusters make Rli1p a target of a number of major stressors, and that the essentiality of Rli1p means that such targeting is a cause of cell death during stress. The work programme will involve both screening approaches and specific manipulations to test the hypothesis. We will examine Rli1p function over a wide range of stress conditions. We will also exploit the power of yeast genetics to identify cellular factors that impact Rli1p function during stress. In addition, we will elucidate the mechanism(s) of Rli1p targeting. These studies are important as Rli1p has not been examined previously in this context, yet the evidence we discuss indicate that Rli1p is likely to be a major player in determining the abilities of organisms to cope with certain stresses. Elucidation of that role is vital if this research may be exploited for improving biotechnological processes or health in the future.