西亚试剂：The clathrin adaptor Numb regulates intestinal cholesterol

发布时间：2025-12-19

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

Pei-Shan Li，  Zhen-Yan Fu，  Ying-Yu Zhang，  Jin-Hui Zhang，  Chen-Qi Xu，  Yi-Tong Ma，  Bo-Liang Li  & Bao-Liang Song

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) protein1， 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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