Regulation of VPS34 Kinase in Response to Starvation

* 细胞对营养物质可用性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至关重要。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“自食”）。 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物质。 在这个过程中最重要的酶之一是脂质激酶VPS34，其磷酸化形成破坏性自噬囊泡所需的脂质。 我们最近发现，在另一种称为内体的囊泡上，VPS34对脂质的磷酸化也是饥饿条件下生存所必需的。 这是非常有趣的，因为内体没有直接产生能量的方式或已知的减少能量消耗的方式。** 在这项研究计划中，我们将了解细胞如何将信息传递给内体VPS34，以及这种调节的下游效应是什么。 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，几乎所有关于这种激酶的研究都是关于它在自噬途径中的作用。 这也很有趣，因为我们可以看到，去除不同的营养素都具有降低内体VPS34激酶效率的相同效果，表明这种类型的调节可能是饥饿反应的核心方面。从这项研究向前推进，我们将确定这一途径如何与其他代谢应激反应相互作用，寻找串扰或反馈。 我们还将把我们的代谢研究从细胞水平转移到生物体水平，以更全面地了解不同组织和营养限制形式中的这一过程。 这些研究将填补我们对哺乳动物饥饿反应理解的重要空白。

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.**