Inpanathan Subothan, Botelho Roberto J
Department of Chemistry and Biology, Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada.
Front Cell Dev Biol. 2019 Jun 20;7:113. doi: 10.3389/fcell.2019.00113. eCollection 2019.
Lysosomes are the terminal degradative compartment of autophagy, endocytosis and phagocytosis. What once was viewed as a simple acidic organelle in charge of macromolecular digestion has emerged as a dynamic organelle capable of integrating cellular signals and producing signal outputs. In this review, we focus on the concept that the lysosome surface serves as a platform to assemble major signaling hubs like mTORC1, AMPK, GSK3 and the inflammasome. These molecular assemblies integrate and facilitate cross-talk between signals such as amino acid and energy levels, membrane damage and infection, and ultimately enable responses such as autophagy, cell growth, membrane repair and microbe clearance. In particular, we review how molecular machinery like the vacuolar-ATPase proton pump, sestrins, the GATOR complexes, and the Ragulator, modulate mTORC1, AMPK, GSK3 and inflammation. We then elaborate how these signals control autophagy initiation and resolution, TFEB-mediated lysosome adaptation, lysosome remodeling, antigen presentation, inflammation, membrane damage repair and clearance. Overall, by being at the cross-roads for several membrane pathways, lysosomes have emerged as the ideal surveillance compartment to sense, integrate and elicit cellular behavior and adaptation in response to changing environmental and cellular conditions.
溶酶体是自噬、内吞作用和吞噬作用的终末降解区室。曾经被视为负责大分子消化的简单酸性细胞器，如今已成为一个能够整合细胞信号并产生信号输出的动态细胞器。在本综述中，我们重点关注溶酶体表面作为一个平台来组装主要信号枢纽（如mTORC1、AMPK、GSK3和炎性小体）的概念。这些分子组装整合并促进诸如氨基酸和能量水平、膜损伤和感染等信号之间的相互作用，最终引发如自噬、细胞生长、膜修复和微生物清除等反应。特别是，我们综述了诸如液泡 - ATP酶质子泵、 sestrins、GATOR复合体和Ragulator等分子机制如何调节mTORC1、AMPK、GSK3和炎症。然后我们详细阐述了这些信号如何控制自噬的起始和终止、TFEB介导的溶酶体适应、溶酶体重塑、抗原呈递、炎症、膜损伤修复和清除。总体而言，由于处于多种膜途径的交叉点，溶酶体已成为感知、整合并引发细胞行为和适应以应对不断变化的环境和细胞条件的理想监测区室。
