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.

项目概要/摘要 受体的内化和再循环是所有真核细胞的关键生物过程。早期/排序 内体是从质膜 (PM) 内化的受体的最初目的地，并充当 主要分选站，受体从中分流到晚期内体和溶酶体进行降解，或 通过囊泡和管状回收内体的短暂网络回收回 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至降解途径，目标是 回收途径在很大程度上被认为是默认发生的被动过程。然而，最近 有证据支持通过特定分选连接蛋白 (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 这是所有哺乳动物细胞的重要过程，但对其调节的复杂性知之甚少，包括 内体膜上受体的分类，囊泡和小管的出芽和分裂 内体，以及将受体转运回 PM。因此，我们对内体功能的了解滞后 明显落后于受体内化机制。 控制内体分选和运输的一组关键调节蛋白是逆转录体复合物。 逆转录酶最初是在从内体到高尔基复合体的生物合成货物的检索中发现的， 最近涉及范围内外多种关键细胞途径的调节 内吞运输，包括内吞再循环、线粒体稳态、中心体循环和 纤毛发生。逆转录酶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，其相互作用伴侣和内体裂变调节剂，Eps15 同源性 结构域蛋白 1 (EHD1) 和一系列介导内体货物分选的分选连接蛋白 SNX 蛋白。 Retromer 还通过 WASH 复合物与肌动蛋白细胞骨架连接。我们的实验室一直专注于 全面了解内吞调节蛋白在内吞中发挥作用的机制 途径和非内吞贩运。特别是，我们将解决重大且尚未解决的问题 生物学问题，例如：i) 内体裂变如何调节以及如何与分类和回收相关，以及 ii) 关键内吞蛋白如何介导初级纤毛的生物发生。