The role of OCRL1 in endocytic membrane traffic

OCRL1在内吞膜运输中的作用

• 批准号: MR/K000810/1
• 负责人: Martin Lowe
• 金额: $ 68.37万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK000810%2F1
• 关键词: role; OCRL1; endocytic; membrane; traffic

The cells in our body are made up of internal membrane-enclosed compartments called organelles, each with their own identity and specific functions. Material is transferred between the organelles and between certain organelles and the outside of the cell via a process termed membrane traffic. One of the major membrane traffic pathways is the endocytic pathway, where material is taken up from the cell exterior via engulfment in membrane-enclosed vesicles at the cell surface. The internalised material is then sorted to various downstream compartments or recycled back to the cell surface. The endocytic pathway is fundamentally important to all cells, and when defective gives rise to numerous diseases in humans. Moreover, this pathway is exploited by pathogenic viruses and bacteria to gain entry into cells to cause infection. It is therefore important we understand how the endocytic pathway functions at the molecular level. This proposal is focussed on two enzymes that are localised to organelles within the endocytic pathway, called OCRL1 and INPP5B. These enzymes act on a class of lipids called phosphoinositides that are important for controlling various aspects of cell behaviour including endocytic membrane traffic. Mutation of OCRL1 causes two diseases in humans, called Lowe syndrome and Dent-2 disease, which are characterised by defective brain, eye and kidney function. The mechanisms by which mutation of OCRL1 brings about the pathological changes seen in Lowe and Dent patients remain unclear. We have identified a new binding partner for OCRL1 and INPP5B called IPIP27A that is essential for trafficking within the endocytic pathway. The aim of this proposal is now to determine how IPIP27A functions together with its interaction partners to regulate endocytic trafficking. Our hypothesis is that OCRL1/INPP5B and IPIP27A participate in the formation of membrane carriers on endocytic organelles to ensure trafficking occurs in a properly controlled manner. How this process occurs remains poorly understood. We plan to use a combination of experimental approaches to dissect the mechanisms involved. This will entail analysis of endocytic trafficking in tissue culture cells using various established methods including imaging of living cells in real time. Our work will provide important knowledge as to how the endocytic pathway functions in all cells, as well as reveal the mechanisms underlying Lowe syndrome, Dent disease and other disorders caused by defects in endocytic trafficking.

我们体内的细胞由称为细胞器的内部膜封闭区室组成，每个细胞器都有自己的身份和特定功能。物质通过称为膜运输的过程在细胞器之间以及某些细胞器与细胞外部之间转移。主要的膜运输途径之一是内吞途径，其中物质通过吞噬在细胞表面的膜封闭囊泡中从细胞外部摄取。然后内化的材料被分类到各个下游隔室或回收回到细胞表面。内吞途径对所有细胞都至关重要，当内吞途径出现缺陷时，会导致人类多种疾病。此外，病原病毒和细菌利用该途径进入细胞引起感染。因此，我们了解内吞途径如何在分子水平上发挥作用非常重要。该提案的重点是定位于内吞途径内细胞器的两种酶，称为 OCRL1 和 INPP5B。这些酶作用于一类称为磷酸肌醇的脂质，对于控制细胞行为的各个方面（包括内吞膜运输）非常重要。 OCRL1 突变会导致人类患两种疾病，称为 Lowe 综合征和 Dent-2 病，其特征是大脑、眼睛和肾功能缺陷。 OCRL1 突变导致 Lowe 和 Dent 患者出现病理变化的机制仍不清楚。我们已经确定了 OCRL1 和 INPP5B 的一个新的结合伙伴，称为 IPIP27A，它对于内吞途径中的运输至关重要。该提案的目的现在是确定 IPIP27A 如何与其相互作用伙伴一起发挥作用来调节内吞贩运。我们的假设是 OCRL1/INPP5B 和 IPIP27A 参与内吞细胞器上膜载体的形成，以确保运输以适当控制的方式发生。这个过程是如何发生的仍然知之甚少。我们计划结合使用实验方法来剖析所涉及的机制。这将需要使用各种既定方法（包括实时活细胞成像）对组织培养细胞中的内吞运输进行分析。我们的工作将提供有关内吞途径如何在所有细胞中发挥作用的重要知识，并揭示 Lowe 综合征、Dent 病和内吞运输缺陷引起的其他疾病的潜在机制。

项目成果

OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates.

• DOI: 10.1091/mbc.e15-06-0329
• 发表时间: 2016-01-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Billcliff PG;Noakes CJ;Mehta ZB;Yan G;Mak L;Woscholski R;Lowe M
• 通讯作者: Lowe M

The cellular and physiological functions of the Lowe syndrome protein OCRL1.

• DOI: 10.1111/tra.12160
• 发表时间: 2014-05
• 期刊: Traffic (Copenhagen, Denmark)
• 作者: Mehta ZB;Pietka G;Lowe M
• 通讯作者: Lowe M