期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：41
DOI：10.1073/pnas.2113174118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Lysosomes are organelles that also act as cell-signaling hubs. They regulate functions ranging from antigen presentation to autophagy. Spherical lysosomes can spontaneously elongate into tubules in starving or inflamed immune cells. We describe a DNA-based reagent, denoted
Tudor, that tubulates lysosomes in macrophages without triggering either an immune response or autophagy. Chemical imaging revealed that tubular lysosomes differ from vesicular ones in terms of their pH, calcium, and proteolytic activity.
Tudor revealed a role for tubular lysosomes in that they enhance MMP9 secretion and phagocytosis in resting macrophages. The ability to tubulate lysosomes in resting immune cells without starving or inflaming them may help reveal new insights into how tubular lysosomes function.
Lysosomes adopt dynamic, tubular states that regulate antigen presentation, phagosome resolution, and autophagy. Tubular lysosomes are studied either by inducing autophagy or by activating immune cells, both of which lead to cell states where lysosomal gene expression differs from the resting state. Therefore, it has been challenging to pinpoint the biochemical properties lysosomes acquire upon tubulation that could drive their functionality. Here we describe a DNA-based assembly that tubulates lysosomes in macrophages without activating them. Proteolytic activity maps at single-lysosome resolution revealed that tubular lysosomes were less degradative and showed proximal to distal luminal pH and Ca
2+ gradients. Such gradients had been predicted but never previously observed. We identify a role for tubular lysosomes in promoting phagocytosis and activating MMP9. The ability to tubulate lysosomes without starving or activating immune cells may help reveal new roles for tubular lysosomes.
