Characterisation of the PI3P-dependent signalling network responsible for nutrient sensing and autophagy

细胞健康生长最重要的要求之一是感知和响应细胞外营养的能力。当营养供应充足时，细胞只需微调合成代谢和分解代谢的速率，使其能量需求与可用的资源相匹配。当营养素变得有限或完全不可用时，需要更强大的行动方案才能让细胞存活。在这样的营养撤退时期，细胞通过启动自噬做出反应，这是一种降解途径，允许细胞内的蛋白质分解为氨基酸，随后可用于新的蛋白质合成或能量生成。自噬中的一个重要问题与细胞感知其胞外营养含量的机制有关。许多研究小组最近的研究表明，一种名为磷脂酰肌醇3磷酸(PI3P)的小分子脂质分子是营养感知的重要信号。我们自己的工作也表明，自噬的诱导部分是由于被称为omegasome的特殊膜间隔中PI3P的形成。因此，在自噬早期产生PI3P的机制和信号可能为通过营养感应控制自噬提供重要信息。这笔赠款的目的是识别参与这一途径的所有人类基因。我们计划系统地沉默所有已知的人类基因，然后观察这将在自噬过程中形成PI3P的效果。通过识别所有这样的基因，我们将能够构建与营养感知有关的细胞通路的连线图，并通过诱导自噬来响应营养限制。

One of the most important requirements for healthy cellular growth is the ability to sense and respond to extracellular nutrients. When nutrient supply is plentiful, cells need only to fine tune their anabolic and catabolic rates so that their energy requirements match the available resources. When nutrients become limiting or are completely unavailable, a much stronger course of action is required to allow the cells to survive. During such times of nutrient withdrawal, the cells respond by initiating autophagy, a degradative pathway that allows the breakdown of intracellular proteins into amino acids that can be used subsequently for new protein synthesis or energy generation. An important question in autophagy concerns the mechanisms by which cells sense their extracellular nutrient content. Recent work from many groups has indicated that a small lipid molecule termed phosphatidylinositol 3 phosphate (PI3P) is an important signal for nutrient sensing. Our own work also indicates that autophagy is induced partially as a result of the formation of PI3P in specialised membrane compartments called omegasomes. Therefore, the mechanisms and signals that generate PI3P early during autophagy are likely to provide important information on the control of autophagy by nutrient sensing. The aim of this grant is to identify all human genes that are involved in this pathway. We plan to systematically silence all known human genes and then look at the effect that this will have in formation of PI3P during autophagy. By identifying all such genes we will be able to construct a wiring diagram of the cellular pathways that are implicated in nutrient sensing and respond during nutrient limitation by the induction of autophagy.