The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1

	The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1
	Li, PS; Fu, ZY; Zhang, YY; Zhang, JH; Xu, CQ; Ma, YT; Li, BL; Song, BL
刊名	NATURE MEDICINE
	2014
卷号	20 期号:1 页码:80-+
通讯作者	Song, BL (reprint author), Chinese Acad Sci, State Key Lab Mol Biol, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai, Peoples R China.,blsong@sibcb.ac.cn
英文摘要	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.
学科主题	Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine
类目[WOS]	Biochemistry & Molecular Biology ; Cell Biology ; Medicine, Research & Experimental
关键词[WOS]	FATE DETERMINANT NUMB ; N-TERMINAL DOMAIN ; UBIQUITIN LIGASE ; EZETIMIBE BLOCKS ; MAMMALIAN NUMB ; PROTEIN ; BINDING ; INTERNALIZATION ; PHOSPHORYLATION ; IDENTIFICATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000329349400023
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/133]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Li, PS,Fu, ZY,Zhang, YY,et al. The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1[J]. NATURE MEDICINE,2014,20(1):80-+.
APA	Li, PS.,Fu, ZY.,Zhang, YY.,Zhang, JH.,Xu, CQ.,...&Song, BL.(2014).The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1.NATURE MEDICINE,20(1),80-+.
MLA	Li, PS,et al."The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1".NATURE MEDICINE 20.1(2014):80-+.