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; 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.

项目摘要/摘要 受体的内在化和回收是所有真核细胞中的关键生物学过程。早期/分类 内体是从质膜（PM）内化的受体的初始目的地，并用作 主要分类站，从中分流到后期内体和溶酶体降解或 通过囊泡和管状回收内体的短暂网络回收回到PM。而a 十年前，大多数研究人员认为，主动对定向蛋白质的主动分类为降解途径，针对性 人们认为，回收道路被认为是默认情况下发生的一个被动过程。但是，最近 证据支持通过特定排序Nexin（SNX）和其他蛋白质对回收途径进行主动排序 与受体的细胞质尾巴结合，并专门针对它们进行回收。虽然回收是 所有哺乳动物细胞的基本过程，其调节的复杂性尚不清楚，包括 在内体膜上分类受体，囊泡和小管的萌芽和裂变 内体，以及受体的传输回到PM。因此，我们对内体功能的了解滞后 显着落后于受体内在化机制。 控制内体的分类和运输的关键调节蛋白是逆转录络合物。 最初在从内体到高尔基体综合体的生物合成货物的检索中鉴定出 最近与范围内外的多种关键细胞通路有关 内吞交易，包括内吞回收，线粒体稳态，中心体周期和 纤毛发生。逆转录复合物还与其他关键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 域蛋白1（EHD1），以及介导内体货物分类的大量分类Nexin SNX蛋白。 逆转录器还通过洗涤络合物链接到肌动蛋白细胞骨架。我们的实验室一直专注于 对内吞调节蛋白在内吞作用的机制的总体理解 途径和非注入型贩运。特别是，我们将解决重要的，尚未解决的问题 生物学问题，例如：i）如何调节内体裂变并与分类和回收利用，以及II） 关键内吞蛋白如何介导原发性纤毛的生物发生。