Autophagy transcriptional crosstalk: the LMX1A/LMX1B paradigm

自噬是所有细胞进行的一个重要的质量控制过程，以帮助它们发挥正常的生物学功能，并保护它们免受作为多细胞生命一部分的不可避免的压力。它涉及到将受损和潜在有害的细胞物质包装到结合在膜上的囊(称为自噬小体)中，然后运送到细胞的废物处理中心。因此，自噬是整个生命周期中正常组织动态平衡的一个关键方面，也是预防包括神经退化、心脏病、糖尿病和癌症在内的重要人类疾病的关键保护者。近年来，关于自噬过程是如何在细胞内被调控的--最终在2016年将诺贝尔奖授予该领域的先驱之一--大滨义典教授--我们已经了解了很多，但我们对监督自噬过程的基因如何对压力做出反应知之甚少。基因表达的过程(开启基因)涉及到被称为转录因子的蛋白质与细胞DNA上的激活位点的结合。我们已经发现，一对重要的转录因子-称为LMX1a和Lmx1b-启动关键的自噬基因，以帮助肾脏和大脑(部分)等重要器官中细胞的形成和功能。在确认了这些转录因子在自噬基因表达中的作用后，挑战一直是更好地了解它们本身是如何调控的。令人惊讶的是，我们发现形成自噬所需的一种关键蛋白质--称为LC3--与LMX1a/Lmx1b结合，以增强它们刺激自噬基因表达的能力，这意味着自噬机制可以通过启动自己的基因来控制自己。在这项提议中，我们的目标是提供这一令人兴奋的发现的核心分子机制的清晰图景，通过这样做，我们将确定这一新的场景是否扩展到其他自噬和相关的转录因子，作为更好地了解细胞如何应对整个生命周期的压力和挑战的协同努力的一部分。这是一个前沿生物科学项目，旨在了解细胞生物学的基本过程。也就是说，自噬对于人类、动物和植物的正常健康是必不可少的，在发育的不同阶段都是必需的，并有助于保持组织在衰老期间的正常功能。出于这个原因，人们正在积极研究自噬，将其作为治疗各种与衰老有关的疾病的有效药物靶点，特别是神经退化和癌症，并将其作为提高作物产量和生物工程的一种途径。我们努力更好地了解人类自噬基因表达途径中的潜在串扰，这有可能被用于疾病治疗，因此，我们将研究我们发现的新途径如何影响脑(神经元)和肾(足细胞)细胞模型中重要细胞类型的健康。

Autophagy is an important quality control process carried out by all cells to assist with their normal biological functions and to protect them from the stresses they inevitably encounter as part of multicellular life. It involves the packaging of damaged and potentially harmful cellular material into membrane-bound sacs (called autophagosomes) for delivery to the waste disposal centre of the cell. For this reason, autophagy is a key facet of normal tissue homeostasis across the lifespan, and is a critical protector against important human diseases including neurodegeneration, heart disease, diabetes and cancer. Over recent years we have learned much about how the autophagy process is regulated within cells - culminating in the award of a Nobel Prize in 2016 to Prof. Yoshinori Ohsumi, one of the pioneers in the field - but we still know relatively little about how the genes that oversee the autophagy process are controlled in response to stress. The process of gene expression (switching genes on) involves the binding of proteins called transcription factors to activating sites on the cell's DNA. We have found that an important pair of transcription factors - called LMX1A and LMX1B - switch on critical autophagy genes to help with the formation and function of cells in important organs such as the kidney and (parts of) the brain. Having confirmed roles for these transcription factors during autophagy gene expression, the challenge has been to better understand how they are themselves regulated. Surprisingly, we have discovered that a key protein needed for the formation of autophagosomes - called LC3 - binds to LMX1A/LMX1B to increase their ability to stimulate autophagy gene expression, meaning that the autophagy machinery can potentially control itself by switching on its own genes. In this proposal we aim to provide a clear picture of the molecular mechanisms central to this exciting finding, and by doing so we will determine whether this novel scenario extends to other autophagy and related transcription factors as part of concerted efforts to better understand how cells cope with stresses and challenges across the lifespan.This is a frontier bioscience project that seeks to understand fundamental processes in cell biology. That said, autophagy is essential for normal health in humans, animals and plants, being required during various stages of development and helping to keep tissues functioning normally during ageing. For this reason, autophagy is being vigorously researched as a potent pharmaceutical target in various diseases associated with ageing, notably neurodegeneration and cancer, and as a route to improve crop productivity and in bioengineering. Our efforts to better understand the potential crosstalk within the autophagy gene expression pathways in humans has the potential to be exploited in disease therapy, and for our part we will therefore examine how the novel pathway we have discovered impacts on the health of important cell types in brain (neurons) and kidney (podocytes) cell models.