Regulation of membrane trafficking by Coronins

Coronins 对膜运输的调节

• 批准号: 10398239
• 负责人: Silvia Jansen
• 金额: $ 33.08万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398239
• 关键词: Actin-Binding Protein; Actins; Address; Adhesions; Affect; Automobile Driving; Autophagocytosis; Autophagosome; Binding; Biochemical; Biological Assay; Biological Process; Biophysics; Cell Shape; Cell physiology; Cells; Cellular biology; Complex; Crystallization; Crystallography; Cytoskeleton; Data; Distant; Family; Fluorescence; Genetic; Glia Maturation Factor; Image; Imaging Techniques; In Vitro; Individual; Intracellular Membranes; Lead; Learning; Length; Light; Lysosomes; Mediating; Membrane; Microfilaments; Modeling; Molecular; Natural Immunity; Neurons; Nutrient; Organelles; Phagocytosis; Play; Process; Protein Biochemistry; Proteins; Pyrenes; Recovery; Regulation; Resolution; Role; Series; Specificity; Speed; Surface; System; Tail; Techniques; Testing; Time; Total Internal Reflection Fluorescent; Transmembrane Transport; Vesicle; Work; base; cell motility; coronin protein; genetic regulatory protein; immunological synapse formation; insight; interdisciplinary approach; live cell imaging; misfolded protein; neurotransmission; overexpression; reconstruction; single molecule; spatiotemporal; trafficking; wound healing

ABSTRACT The extensive family of the Coronins plays an important role in regulating the actin networks that drive cell migration, polarity, cell shape and intracellular trafficking, and thereby contribute to essential biological processes ranging from innate immunity to neuronal signaling. However, these functions and activities have been characterized for the canonical Coronins. In stark contrast, we know next to nothing about the cellular roles and actin cytoskeleton regulation of the structurally distinct class of the tandem Coronins, which comprises Coronin 7 (Coro7), POD-1, and CorB. Our preliminary data show that mammalian Coro7 can control Arp2/3-mediated nucleation, although the mechanism underlying this activity remains elusive. In addition, we show that this actin- regulatory activity can regulate NPF-induced actin networks that drive intracellular membrane transport, including autophagy, a process used by cells to dispose of unwanted organelles, misfolded proteins and toxic aggregates. Using a multidisciplinary approach comprising state-of-the-art biochemical, biophysical, genetic and live-imaging techniques we propose here to elucidate 1) how Coro7 structurally interacts with Arp2/3, 2) how Coro7 mechanistically inhibits Arp2/3-mediated nucleation by nucleation promoting factors, and 3) by other Arp2/3 regulators, and 4) how these actin-regulatory activities of Coro7 regulate the turnover of the branched actin networks that drive autophagy.

抽象的 冠状素的广泛家族在调节肌动蛋白方面起着重要作用 驱动细胞迁移，极性，细胞形状和细胞内运输的网络以及 因此有助于从先天免疫到 神经元信号传导。但是，这些功能和活动的特征是 规范的冠状蛋白。与之形成鲜明对比的是，我们几乎一无所知 串联的结构不同类别的角色和肌动蛋白细胞骨架调节 冠状蛋白包括冠状7（Coro7），Pod-1和Corb。我们的初步数据 表明哺乳动物Coro7可以控制ARP2/3介导的成核，尽管 该活动的基础机制仍然难以捉摸。此外，我们表明这种肌动蛋白 - 调节活动可以调节NPF诱导的肌动蛋白网络，以驱动细胞内 膜运输，包括自噬，细胞用于处置的过程 不需要的细胞器，错误折叠的蛋白质和有毒骨料。使用多学科 包括最先进的生化，生物物理，遗传和现场成像的方法 我们在这里提出的技术阐明1）Coro7如何与Arp2/3结构相互作用， 2）CORO7如何机械抑制ARP2/3介导的成核的成核。 促进因素，以及3）其他ARP2/3调节剂，以及4）这些肌动蛋白调控如何 CORO7的活动调节驱动的分支肌动蛋白网络的营业额 自噬。