The Regulation of Macropinocytosis

摘要： 大胞质小体是相对较大的内吞囊泡，几乎在所有生长阶段都会形成。 通过质膜和肌动蛋白细胞骨架的运动而产生的后生动物细胞 微管依赖膜融合将细胞外溶质输送到溶酶体内 反应。巨噬细胞增多症是许多致病细菌和病毒入侵的途径。 宿主细胞，采集抗原以启动免疫反应，细胞外营养物质 摄入以支持K-RAS转化的癌细胞的生长。斯旺森实验室的研究 介绍了有关巨噬细胞增多的基本概念，包括膜如何 磷脂修饰酶和细胞骨架活性协调大针体 形成，大针体如何将生长信号从细胞表面受体传递到 雷帕霉素复合体-1(MTORC1)在溶酶体膜上的作用靶点及其机制 巨噬细胞吞噬作用限制了激活的巨噬细胞中溶酶体膜的损伤。尽管 认识到巨噬细胞增多症在健康和疾病中的重要性以及相当大的 在了解其机制和监管方面取得进展，但仍存在重大问题 未回答：(1)1型磷脂酰肌醇3-激酶是如何组织巨噬细胞杯状结构的 巨噬细胞闭合？(2)Src家族蛋白激酶如何调节巨噬细胞增多？(3) 什么分子或活动决定了大胞质小体是否提供其溶质含量 进入溶酶体还是再循环到细胞表面？(4)细胞营养状况如何？ 巨噬细胞吞噬对溶质积累有影响吗？这项研究项目使用了创新的 细胞生物学、分子遗传学和定量显微镜的方法来回答这些问题 基本问题。这项研究的继续将使巨噬细胞增多 细胞生长、代谢和先天免疫的背景，并可能导致新的治疗方法 癌症、传染病和免疫系统紊乱的治疗方法。

Abstract: Macropinosomes are relatively large endocytic vesicles which form in nearly all growing metazoan cells by movements of plasma membrane and the actin cytoskeleton, and which deliver extracellular solutes into lysosomes by microtubule-dependent membrane fusion reactions. Macropinocytosis is the route by which many pathogenic bacteria and viruses invade host cells, antigen is sampled for initiation of immune responses, and extracellular nutrients are ingested to support the growth of K-Ras-transformed cancer cells. Research in the Swanson lab has introduced foundational concepts about macropinocytosis, including how membrane phospholipid-modifying enzymes and cytoskeletal activities coordinate macropinosome formation, how macropinosomes transmit growth signals from cell surface receptors to the mechanistic target of rapamycin complex-1 (mTORC1) on lysosomal membranes, and how macropinocytosis limits damage to lysosomal membranes in activated macrophages. Despite the recognized importance of macropinocytosis in health and disease, and the considerable progress in understanding its mechanism and regulation, significant questions remain unanswered: (1) How does type 1 phosphatidylinositol 3-kinase organize macropinocytic cup closure into macropinosomes? (2) How do Src-family kinases regulate macropinocytosis? (3) What molecules or activities determine whether macropinosomes deliver their solute contents into lysosomes or recycle them to the cell surface? (4) How does cellular nutrient status influence solute accumulation by macropinocytosis? This research program uses innovative approaches to cell biology, molecular genetics and quantitative microscopy to answer these fundamental questions. The continuation of this research will put macropinocytosis into the context of cell growth, metabolism and innate immunity, and could lead to new therapeutic approaches to cancer, infectious diseases and disorders of the immune system.