A mechanism of self-lipid endocytosis mediated by the receptor Mincle.
Alexey V KostarnoyPetya G GanchevaIgor I KireevAndrey I SolovyevBernd LepeniesAndrey Y KulibinEkaterina A MalolinaOlga N ScheglovitovaAlexey V KondratevMaria V SokolovaDaria VorobyevaNadezhda FilippovaMarina R KapkaevaMaria A LagarkovaPavel S MetalnikovEvgeniy RiabenkoDaniil A GrumovMaxim A BobrovElena VasilievaBoris S NaroditskyAlexander L GintsburgPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- fatty acid
- endothelial cells
- type diabetes
- cardiovascular disease
- metabolic syndrome
- induced apoptosis
- multiple sclerosis
- quantum dots
- weight loss
- single molecule
- insulin resistance
- squamous cell carcinoma
- cell proliferation
- single cell
- signaling pathway
- high throughput
- adipose tissue
- vascular endothelial growth factor
- mass spectrometry
- weight gain
- subarachnoid hemorrhage
- cerebral ischemia
- wild type