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室组成，每个隔室具有自己的身份和特定功能。材料通过称为膜流量的过程在细胞器之间，某些细胞器和细胞外部之间传递。主要的膜交通途径之一是内吞途径，在该通路中，材料在细胞表面的膜封闭的囊泡中从细胞外部取走。然后将内部化的材料分类到各种下游室或回收回到细胞表面。内吞途径对所有细胞根本重要，并且当缺陷引起人类疾病时。此外，该途径被致病性病毒和细菌所利用，以进入细胞以引起感染。因此，重要的是我们了解内吞途径如何在分子水平上起作用。该建议集中在两个酶的酶上，这些酶位于内吞途径内的细胞器，称为OCRL1和INPP5B。这些酶对一类称为磷酸肌醇的脂质作用，这些酶对于控制包括内吞膜流量在内的各个方面很重要。 OCRL1的突变引起人类的两种疾病，称为Lowe综合征和Dent-2疾病，这些疾病的特征是大脑，眼睛和肾功能有缺陷。 OCRL1突变带来Lowe和Dent患者所看到的病理变化的机制尚不清楚。我们已经确定了一个名为IPIP27A的OCRL1和INPP5B的新结合伙伴，这对于在内吞途径内运输至关重要。该提案的目的现在是确定IPIP27A如何运作及其相互作用伙伴以调节内吞贩运。我们的假设是OCRL1/INPP5B和IPIP27A参与内吞器细胞器上的膜载体形成，以确保以正确控制的方式进行贩运。这种过程的发生方式仍然很糟糕。我们计划使用实验方法的组合来剖析所涉及的机制。这将需要使用各种已建立的方法（包括实时的活细胞成像）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在所有细胞中如何发挥作用的重要知识，以及揭示Lowe综合征，凹陷疾病和其他因内吞流量缺陷引起的疾病的机制。

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