Organelle dynamics and function in the late endocytic pathway

晚期内吞途径中的细胞器动力学和功能

• 批准号: MR/R009015/1
• 负责人: Paul Luzio
• 金额: $ 59.05万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR009015%2F1
• 关键词: Organelle; dynamics; function; late; endocytic

Cells are compartmentalized by specialized organelles (little organs within each cell), and cargo including proteins is moved between these compartments by the trafficking of vesicles (little bubbles surrounded by a thin membrane made of a fatty substance called phospholipid and studded with proteins). Some of the cargo is taken up into the cells by vesicles formed at the cell surface that deliver their cargo to organelles called endosomes, endolysosomes and lysosomes. Lysosomes act as storage organelles for enzymes that degrade cargo that is delivered from the cell surface or other parts of the cell. Degradation occurs in endolysosomes formed by the fusion of endosomes with lysosomes. Lysosomes are regenerated from endolysosomes by a process that is currently poorly understood and which we will study. These lysosomes can then be re-used. We aim to identify and study the proteins that make up the machinery necessary to achieve and regulate the regeneration of lysosomes. Our work will help us to understand much better why the organelles we are studying are so dynamic and to explain how the environment within them is regulated such that endolysosomes are such an efficient site for cargo degradation and lysosomes work so well to store the degradative enzymes. There are many diseases in which defects in the cell surface and/or in membrane traffic to lysosomes occur. These include rare genetic diseases such as the lysosomal storage disorders and more common diseases including diabetes, atherosclerosis and neurodegenerative diseases as well as infectious diseases where microbes subvert the membrane traffic system in order to infect cells. In the long term our work will contribute to developing better ways of targeting drugs to particular sites within cells for more specific drug therapies.

细胞由专门的细胞器（每个细胞内的小器官）分隔，包括蛋白质在内的货物通过囊泡（小气泡被称为磷脂的脂肪物质制成的薄膜包围，并充满蛋白质）的运输在这些隔间之间移动。一些货物被细胞表面形成的囊泡吸收到细胞中，这些囊泡将货物运送到称为内体、内溶酶体和溶酶体的细胞器。溶酶体充当酶的储存器，所述酶降解从细胞表面或细胞的其他部分递送的货物。降解发生在由内体与溶酶体融合形成的内溶酶体中。溶酶体是通过一个目前知之甚少的过程从内溶酶体再生的，我们将对此进行研究。然后这些溶酶体可以重新使用。我们的目标是识别和研究构成实现和调节溶酶体再生所需机制的蛋白质。我们的工作将帮助我们更好地理解为什么我们正在研究的细胞器如此动态，并解释它们内部的环境是如何调节的，使得内溶酶体是货物降解的有效场所，而溶酶体则可以很好地储存降解酶。存在许多疾病，其中发生细胞表面和/或膜运输至溶酶体的缺陷。这些疾病包括罕见的遗传性疾病，如溶酶体贮积症和更常见的疾病，包括糖尿病、动脉粥样硬化和神经退行性疾病以及感染性疾病，其中微生物破坏膜运输系统以感染细胞。从长远来看，我们的工作将有助于开发更好的方法，将药物靶向细胞内的特定部位，以进行更特异的药物治疗。

项目成果

Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29.

• DOI: 10.1038/s41467-020-18773-2
• 发表时间: 2020-10-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Crawley-Snowdon H;Yang JC;Zaccai NR;Davis LJ;Wartosch L;Herman EK;Bright NA;Swarbrick JS;Collins BM;Jackson LP;Seaman MNJ;Luzio JP;Dacks JB;Neuhaus D;Owen DJ
• 通讯作者: Owen DJ

Organelle tethering, pore formation and SNARE compensation in the late endocytic pathway.

• DOI: 10.1242/jcs.255463
• 发表时间: 2021-05-15
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Davis LJ;Bright NA;Edgar JR;Parkinson MDJ;Wartosch L;Mantell J;Peden AA;Luzio JP
• 通讯作者: Luzio JP

Reversible assembly and disassembly of V-ATPase during the lysosome regeneration cycle.

溶酶体再生周期中 V-ATP 酶的可逆组装和分解。

• DOI: 10.17863/cam.106810
• 发表时间: 2024
• 作者: Sava I

Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.

• DOI: 10.1002/humu.24479
• 发表时间: 2022-12
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Pavlova, Elena, V;Lev, Dorit;Michelson, Marina;Yosovich, Keren;Michaeli, Hila Gur;Bright, Nicholas A.;Manna, Paul T.;Dickson, Veronica Kane;Tylee, Karen L.;Church, Heather J.;Luzio, J. Paul;Cox, Timothy M.
• 通讯作者: Cox, Timothy M.

A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export.

三聚体 Rab7 GEF 控制 NPC1 依赖性溶酶体胆固醇输出。

• DOI: 10.17863/cam.57698
• 发表时间: 2020
• 作者: Van Den Boomen D