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：2022
卷号：119
期号：30
DOI：10.1073/pnas.2120489119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Dysregulation of lipid endocytosis, a normal physiological process of cellular lipid uptake, often underlies the pathogenesis of some widespread diseases such as atherosclerosis, obesity, and diabetes. However, the mechanisms of lipid endocytosis are incompletely understood, and only a few such mechanisms have been discovered, limiting the available therapeutic strategies and targets in these diseases. Here we found that the receptor Mincle, previously known as a pattern recognition receptor of the innate immune system, plays a significant role in endocytosis. The results have revealed a fundamental pathway of lipid endocytosis, which we call Mincle-mediated endocytosis.
Cellular lipid uptake (through endocytosis) is a basic physiological process. Dysregulation of this process underlies the pathogenesis of diseases such as atherosclerosis, obesity, diabetes, and cancer. However, to date, only some mechanisms of lipid endocytosis have been discovered. Here, we show a previously unknown mechanism of lipid cargo uptake into cells mediated by the receptor Mincle. We found that the receptor Mincle, previously shown to be a pattern recognition receptor of the innate immune system, tightly binds a range of self-lipids. Moreover, we revealed the minimal molecular motif in lipids that is sufficient for Mincle recognition. Superresolution microscopy showed that Mincle forms vesicles in cytoplasm and colocalizes with added fluorescent lipids in endothelial cells but does not colocalize with either clathrin or caveolin-1, and the added lipids were predominantly incorporated in vesicles that expressed Mincle. Using a model of ganglioside GM3 uptake in brain vessel endothelial cells, we show that the knockout of Mincle led to a dramatic decrease in lipid endocytosis. Taken together, our results have revealed a fundamental lipid endocytosis pathway, which we call Mincle-mediated endocytosis (MiME), and indicate a prospective target for the treatment of disorders of lipid metabolism, which are rapidly increasing in prevalence.
