Hitchhiking is a novel mechanism of organelle transport

搭便车是细胞器运输的一种新机制

• 批准号: 9768484
• 负责人: Jenna Christensen
• 金额: $ 6.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2020-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768484
• 关键词: Adaptor Signaling Protein; Affect; Alzheimer' s Disease; Animal Model; Aspergillus; Aspergillus nidulans; Binding; Biochemistry; Biological Assay; Biotinylation; Cell physiology; Cells; Co-Immunoprecipitations; Coiled-Coil Domain; Complex; Cytoplasm; Defect; Destinations; Development; Dimensions; Disease; Dynein ATPase; Early Endosome; Endoplasmic Reticulum; Environment; Genetic; Genetic Screening; Goals; Hippocampus (Brain); Homologous Protein; Huntington Disease; In Vitro; Intracellular Transport; Kinesin; Label; Light; Link; Lipids; Location; Mammalian Cell; Maps; Mass Spectrum Analysis; Mediating; Microscopy; Microtubule-Associated Proteins; Microtubules; Modeling; Molds; Molecular; Molecular Machines; Motor; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neurons; Organelles; Parkinson Disease; Prevalence; Proteins; Research; Sedimentation process; Sorting - Cell Movement; Testing; Time; Total Internal Reflection Fluorescent; Ustilago; Work; base; biophysical techniques; cell motility; imaging genetics; lipid transport; live cell imaging; novel; peroxisome; polarized cell; receptor; recruit; single molecule

PROJECT SUMMARY The proper distribution of intracellular cargo is crucial for a wide variety of fundamental cellular processes, and defects in intracellular transport are particularly prevalent in neurodevelopmental and neurodegenerative disorders. However, how cargo transport is precisely organized such that the correct cargo is transported to the right place at the right time is not well understood. The long-term goals of this project are to understand how cargo transport is organized and executed in the cell, and to identify components that are adversely affected in diseased states. The majority of cargo in the cell is transported on microtubule tracks by the motor proteins dynein and kinesin. In the standard dogma of motor-driven transport, cargos are linked directly to motor proteins by adaptor molecules. The motor protein then transports the specific type of cargo to its destination. In contrast to this straightforward model of transport, the Reck-Peterson lab has recently co-discovered a novel mechanism of organelle transport, termed “hitchhiking”. Hitchhiking occurs when one type of cargo, rather than attaching directly to a motor, is tethered to and co-transported with another type of cargo. Our lab found that peroxisomes hitchhike on early endosomes in the model organism Aspergillus nidulans and identified the novel linker PxdA as being required for the co-transport of peroxisomes and early endosomes. However, whether hitchhiking is prevalent transport mechanism used to transport other organelle types and how PxdA mediates hitchhiking remain to be determined. This project will investigate the universality and mechanism of organelle hitchhiking in Aspergillus nidulans and hippocampal neurons using a combination of genetics, live cell imaging, and in vitro biochemistry. My aims are to 1) determine whether PxdA acts as a tether between peroxisomes and early endosomes, or whether it has additional functions, 2) determine whether lipid droplets and endoplasmic reticulum also hitchhike on EEs and if they require PxdA to do so, and 3) investigate whether organelle hitchhiking is conserved in hippocampal neurons and identify the linkers required for organelle hitchhiking in these cells. Together, my work will enhance our understanding of how hitchhiking works at a mechanistic level as well as its prevalence as a form of organelle transport.

项目摘要 细胞内货物的适当分布对于多种基本细胞过程至关重要， 细胞内转运的缺陷在神经发育和神经退行性疾病中特别普遍， 紊乱然而，如何精确地组织货物运输，以便将正确的货物运输到目的地， 正确的时间和正确的地点并没有得到很好的理解。这个项目的长期目标是了解如何 货物运输是在单元中组织和执行的，并识别受到不利影响的组件 病态的国家细胞中的大部分货物通过马达蛋白在微管轨道上运输 动力蛋白和驱动蛋白。在马达驱动运输的标准教条中，货物直接与马达蛋白质相连 通过适配器分子。然后，马达蛋白将特定类型的货物运送到目的地。相比之下 对于这种简单的传输模型，雷克-彼得森实验室最近共同发现了一种新的机制， 一种叫做“搭便车”的运输方式搭便车发生时，一种类型的货物，而不是附加 直接连接到发动机上，系在另一种类型的货物上并与之共同运输。我们的实验室发现过氧化物酶体 搭便车的模式生物构巢曲霉早期内涵体，并确定了新的接头PxdA 作为过氧化物酶体和早期内体的共转运所需。然而，无论搭便车是 用于运输其他细胞器类型的普遍运输机制以及PxdA如何介导搭便车 还有待确定。 本项目将研究构巢曲霉细胞器搭便车现象的普遍性和机制， 海马神经元使用遗传学，活细胞成像和体外生物化学的组合。我的目标是 1）确定PxdA是否作为过氧化物酶体和早期内体之间的系链，或者它是否具有 2）确定脂滴和内质网是否也搭便车在EE上， 它们需要PxdA来完成，3）研究海马中细胞器搭便车是否保守 神经元，并确定这些细胞中细胞器搭便车所需的连接器。我的工作将提高 我们对搭便车如何在机械水平上工作的理解，以及它作为一种细胞器形式的普遍性， 运输