NDLI: FACI is a novel clathrin adaptor protein 2-binding protein that facilitates low-density lipoprotein endocytosis

Content Provider	Springer Nature : BioMed Central
Author	Cheng, Yun Kang, Xiao-Zhuo Chan, Pearl Cheung, Pak-Hin Hinson Cheng, Tao Ye, Zi-wei Chan, Chi-Ping Yu, Cheng-Han Jin, Dong-Yan
Abstract	Background Cholesterol plays a vital role in multiple physiological processes. Cellular uptake of cholesterol is mediated primarily through endocytosis of low-density lipoprotein (LDL) receptor. New modifiers of this process remain to be characterized. Particularly, the role of fasting- and CREB-H-induced (FACI) protein in cholesterol homeostasis merits further investigation. Methods Interactome profiling by proximity labeling and affinity purification − mass spectrometry was performed. Total internal reflection fluorescence microscopy and confocal immunofluorescence microscopy were used to analyze protein co-localization and interaction. Mutational analysis was carried out to define the domain and residues required for FACI localization and function. Endocytosis was traced by fluorescent cargos. LDL uptake in cultured cells and diet-induced hypercholesterolemia in mice were assessed. Results FACI interacted with proteins critically involved in clathrin-mediated endocytosis, vesicle trafficking, and membrane cytoskeleton. FACI localized to clathrin-coated pits (CCP) on plasma membranes. FACI contains a conserved DxxxLI motif, which mediates its binding with the adaptor protein 2 (AP2) complex. Disruption of this motif of FACI abolished its CCP localization but didn’t affect its association with plasma membrane. Cholesterol was found to facilitate FACI transport from plasma membrane to endocytic recycling compartment in a clathrin- and cytoskeleton-dependent manner. LDL endocytosis was enhanced in FACI-overexpressed AML12 cells but impaired in FACI-depleted HeLa cells. In vivo study indicated that hepatic FACI overexpression alleviated diet-induced hypercholesterolemia in mice. Conclusions FACI facilitates LDL endocytosis through its interaction with the AP2 complex.
Related Links	https://cellandbioscience.biomedcentral.com/counter/pdf/10.1186/s13578-023-01023-5.pdf
Ending Page	22
Page Count	22
Starting Page	1
File Format	HTM / HTML
ISSN	20453701
DOI	10.1186/s13578-023-01023-5
Journal	Cell & Bioscience
Issue Number	1
Volume Number	13
Language	English
Publisher	BioMed Central
Publisher Date	2023-04-18
Access Restriction	Open
Subject Keyword	Cell Biology Microbiology Stem Cells Neurobiology Proteomics FACI Cholesterol uptake Low-density lipoprotein receptor Clathrin adaptors Endocytosis Hypercholesterolemia
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7/2023

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