title: The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1.
abstract: Hypercholesterolemia, typically due to excessive cholesterol uptake, is a major risk factor for cardiovascular disease, which is responsible for ∼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, 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.
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Pei-Shan
authors: PS
authors: Li
authors: 1] The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2] Department of Cardiovascular Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
authors: Zhen-Yan
authors: ZY
authors: Fu
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Ying-Yu
authors: YY
authors: Zhang
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Jin-Hui
authors: JH
authors: Zhang
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Chen-Qi
authors: CQ
authors: Xu
authors: Department of Cardiovascular Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
authors: Yi-Tong
authors: YT
authors: Ma
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Bo-Liang
authors: BL
authors: Li
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Bao-Liang
authors: BL
authors: Song
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D005453:Fluorescence; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D015151:Immunoblotting; D007408:Intestinal Absorption / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020798:Two-Hybrid System Techniques
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C482445:Npc1l1 protein, mouse; C106293:Numb protein, mouse; D034741:RNA, Small Interfering; D002784:Cholesterol