期刊
NATURE MEDICINE
卷 20, 期 1, 页码 80-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3417
关键词
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资金
- Ministry of Science and Technology of China [2009CB919000, 2011CB910900, 2012CB524900]
- National Natural Science Foundation of China [30925012, 31230020, 81260041, 81270155, 91213306]
- Shanghai Science and Technology Committee [11JC1414100]
- Xinjiang Science and Technology Department [2013911111]
Hypercholesterolemia, typically due to excessive cholesterol uptake, is a major risk factor for cardiovascular disease, which is responsible for similar to 50% of all deaths in developed societies. Although it has been shown that intestinal cholesterol absorption is mediated by vesicular endocytosis of the Niemann-Pick C1-like 1 (NPC1L1) protein(1,2), the mechanism of sterol-stimulated NPC1L1 internalization is still mysterious. Here, we identified an endocytic peptide signal, YVNXXF (where X stands for any amino acid), in the cytoplasmic C-terminal tail of NPC1L1. Cholesterol binding on the N-terminal domain of NPC1L1 released the YVNXXF-containing region of NPC1L1 from association with the plasma membrane and enabled Numb binding. We also found that Numb, a clathrin adaptor, specifically recognized this motif and recruited clathrin for internalization. Disrupting the NPC1L1-Numb interaction decreased cholesterol uptake. Ablation of Numb in mouse intestine significantly reduced dietary cholesterol absorption and plasma cholesterol level. Together, these data show that Numb is a pivotal protein for intestinal cholesterol absorption and may provide a therapeutic target for hypercholesterolemia.
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