Mechanisms of membrane trafficking in endocytic and non-endocytic pathways

内吞和非内吞途径中的膜运输机制

• 批准号: 10797631
• 负责人: Steven H Caplan
• 金额: $ 15.87万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797631
• 关键词: Actins; Address; Administrative Supplement; Back; Binding Proteins; Biogenesis; Biological; Biological Process; Cell Surface Receptors; Cell division; Cell membrane; Centrosome; Cilia; Complex; Cytoplasmic Tail; Cytoskeleton; Degradation Pathway; Destinations; Endosomes; Eukaryotic Cell; Event; Golgi Apparatus; Health; Homeostasis; Human; Knowledge; Laboratories; Link; Lysosomes; Mammalian Cell; Mediating; Membrane; Mission; Mitochondria; Pathway interactions; Process; Proteins; Public Health; Recycling; Regulation; Research; Research Personnel; Retrieval; Signal Transduction; Sorting; Tertiary Protein Structure; Tubular formation; United States National Institutes of Health; Vesicle; cilium biogenesis; endosome membrane; genetic regulatory protein; improved; late endosome; protein function; receptor; receptor internalization; receptor recycling; scaffold; sorting nexins; trafficking

PROJECT SUMMARY/ABSTRACT The internalization and recycling of receptors is a key biological process in all eukaryotic cells. The early/sorting endosome is the initial destination of receptors internalized from the plasma membrane (PM), and serves as a major sorting station from which receptors are shunted to late endosomes and lysosomes for degradation, or recycled back to the PM through a transitory network of vesicular and tubular recycling endosomes. Whereas a decade ago most researchers thought that active sorting directed proteins to the degradation pathways, targeting to the recycling pathway was thought largely to be a passive process that occurs by default. However, recent evidence supports active sorting to the recycling pathways by specific sorting nexin (SNX) and other proteins that bind to the cytoplasmic tails of receptors and specifically target them for recycling. Although recycling is an essential process for all mammalian cells, the complexities of its regulation are poorly understood including the sorting of receptors on endosomal membranes, the budding and fission of vesicles and tubules from the endosome, and the transport of receptors back to the PM. As such, our knowledge of endosomal function lags significantly behind that of receptor internalization mechanisms. A key group of regulatory proteins that controls sorting and trafficking at the endosome is the retromer complex. Originally identified in the retrieval of biosynthetic cargo from endosomes to the Golgi complex, the retromer has recently been implicated in the regulation of a variety of key cellular pathways both within and outside the scope of endocytic trafficking including endocytic recycling, mitochondrial homeostasis, the centrosome cycle and ciliogenesis. The retromer complex also interacts with other key endocytic regulatory proteins, including the tubular endosome scaffold MICAL-L1, its interaction partner and endosomal fission modulator, Eps15 Homology Domain protein 1 (EHD1), and a host of sorting nexin SNX proteins that mediate endosomal cargo sorting. Retromer also links to the actin cytoskeleton via the WASH complex. Our laboratory has been focusing on an overall understanding of the mechanisms by which endocytic regulatory proteins function both in endocytic pathways and in non-endocytic trafficking. In particular, we will address significant and as-yet-unresolved biological problems such as: i) How endosomal fission is regulated and linked to sorting and recycling, and ii) How key endocytic proteins mediate the biogenesis of the primary cilium.

项目总结/摘要 受体的内化和再循环是所有真核细胞中的关键生物学过程。早期/排序 内体是从质膜（PM）内化的受体的初始目的地，并作为一个内体。 主要分选站，受体从该主要分选站分流到晚期内体和溶酶体进行降解，或 通过囊泡和管状再循环内体的暂时网络再循环回到PM。而一个 十年前，大多数研究人员认为，主动分选将蛋白质引导到降解途径，靶向 人们认为回收途径在很大程度上是一个默认发生的被动过程。但最近的 证据支持通过特异性分选连接蛋白（SNX）和其他蛋白质对回收途径进行主动分选 与受体的细胞质尾部结合，并专门针对它们进行回收。虽然回收是一个 作为所有哺乳动物细胞的基本过程，其调控的复杂性知之甚少，包括 内体膜上受体的分选， 内体，以及受体转运回PM。因此，我们对内体功能的了解 明显落后于受体内化机制。 一组控制内体分选和运输的关键调节蛋白是逆转录复合物。 最初在从核内体到高尔基复合体的生物合成货物的回收中鉴定，逆转录酶具有 最近被牵连在调节各种关键细胞通路内外的范围 包括内吞再循环、线粒体稳态、中心体循环和 纤毛发生逆转录复合物还与其他关键的内吞调节蛋白相互作用，包括 管状内体支架MICAL-L1，其相互作用配偶体和内体分裂调节剂，Eps 15同源性 结构域蛋白1（EHD 1）和介导内体货物分选的分选连接蛋白SNX蛋白的宿主。 逆转录聚合物还通过WASH复合物连接到肌动蛋白细胞骨架。我们的实验室一直致力于 对内吞调节蛋白在内吞调节和内吞调节中发挥作用的机制有了全面的了解， 途径和非内吞运输。特别是，我们将解决重大且尚未解决的问题 生物学问题，如：i）内体分裂如何调节并与分类和回收有关，以及ii） 关键内吞蛋白如何介导初级纤毛的生物发生。