Regulation of VPS34 Kinase in Response to Starvation

层级摘要 细胞对养分供应变化的反应能力对于维持促进生存和平衡能量消耗与摄入量是至关重要的。细胞在饥饿状态下产生能量的最重要方式之一是激活一种称为自噬的过程(字面意思是“自噬”)。在这个过程中，细胞降解其内部的一小部分，以产生生存所需的营养。在这一过程中最重要的酶之一是脂激酶Vps34，它使形成破坏性自噬小泡所需的脂类磷酸化。我们最近发现，Vps34在另一个称为内小体的囊泡上对脂类的磷酸化也是在饥饿下生存所必需的。这很有趣，因为内体没有直接产生能量的方法，也没有已知的减少能量消耗的方法。 在这个研究项目中，我们将了解细胞如何向内体Vps34传递信息，以及这一调控的下游影响是什么。此外，我们将确定这如何促进饥饿下的生存。这是一个令人兴奋的研究领域，因为到目前为止，几乎所有关于该激酶的研究都是关于它在自噬途径中的作用。同样有趣的是，我们可以看到，去除不同的营养物质都会产生相同的效果，降低内体Vps34激酶的效率，这表明这种类型的调节可能是饥饿反应的核心方面。 在这项研究的基础上，我们将确定这一途径是如何与其他代谢应激反应相互作用的，以寻找串扰或反馈。我们还将把代谢研究从细胞水平转移到生物水平，以更全面地了解不同组织和形式的营养限制的这一过程。这些研究将填补我们在理解哺乳动物饥饿反应方面的一个重要空白。

Lay Summary The ability of cells to respond to changes in nutrient availability is essential for the maintenance of promoting survival and balancing energy expenditure with intake. One of the most important ways for cells to generate energy under starvation is to activate a process called autophagy (literally meaning “self-eating”). In this process the cell degrades a small portion of its interior to generate nutrients required for survival. One of the most important enzymes in this process is the lipid kinase VPS34, which phosphorylates lipids required for the formation of the destructive autophagic vesicle. We have recently discovered that the phosphorylation of lipids by VPS34 on another vesicle called the endosome is also required for survival under starvation. This is quite interesting as the endosome has no direct way of generating energy or known way of reducing energy expenditure. In this research program we will find out how the cell transmits information to endosomal VPS34 and what the downstream effects of this regulation are. Moreover, we will determine how this promotes survival under starvation. This is an exciting area of research because up to this point nearly all the studies on this kinase have been on its role in the autophagy pathway. It is also interesting because we can see that taking away different nutrients all have the same effect of reducing the efficiency of the endosomal VPS34 kinase, indicating that this type of regulation is likely a core aspect of the starvation response. Moving forward from this study we will determine how this pathway interacts with other metabolic stress responses looking for cross-talk or feedback. We will also move our metabolic studies from the cellular to the organismal level to get a more comprehensive understanding of this process in different tissues and forms of nutrient restriction. These studies will fill an important gap in our understanding of the mammalian starvation response.