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- Publisher Website: 10.1186/s13578-023-01023-5
- Scopus: eid_2-s2.0-85152959533
- WOS: WOS:000970093600001
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Article: FACI is a novel clathrin adaptor protein 2-binding protein that facilitates low-density lipoprotein endocytosis
Title | FACI is a novel clathrin adaptor protein 2-binding protein that facilitates low-density lipoprotein endocytosis |
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Authors | |
Keywords | Cholesterol uptake Clathrin adaptors Endocytosis FACI Hypercholesterolemia Low-density lipoprotein receptor |
Issue Date | 2023 |
Citation | Cell and Bioscience, 2023, v. 13, n. 1, article no. 74 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/335900 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Cheng, Yun | - |
dc.contributor.author | Kang, Xiao Zhuo | - |
dc.contributor.author | Chan, Pearl | - |
dc.contributor.author | Cheung, Pak Hin Hinson | - |
dc.contributor.author | Cheng, Tao | - |
dc.contributor.author | Ye, Zi wei | - |
dc.contributor.author | Chan, Chi Ping | - |
dc.contributor.author | Yu, Cheng Han | - |
dc.contributor.author | Jin, Dong Yan | - |
dc.date.accessioned | 2023-12-28T08:49:36Z | - |
dc.date.available | 2023-12-28T08:49:36Z | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Cell and Bioscience, 2023, v. 13, n. 1, article no. 74 | - |
dc.identifier.uri | http://hdl.handle.net/10722/335900 | - |
dc.description.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. | - |
dc.language | eng | - |
dc.relation.ispartof | Cell and Bioscience | - |
dc.subject | Cholesterol uptake | - |
dc.subject | Clathrin adaptors | - |
dc.subject | Endocytosis | - |
dc.subject | FACI | - |
dc.subject | Hypercholesterolemia | - |
dc.subject | Low-density lipoprotein receptor | - |
dc.title | FACI is a novel clathrin adaptor protein 2-binding protein that facilitates low-density lipoprotein endocytosis | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1186/s13578-023-01023-5 | - |
dc.identifier.scopus | eid_2-s2.0-85152959533 | - |
dc.identifier.volume | 13 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | article no. 74 | - |
dc.identifier.epage | article no. 74 | - |
dc.identifier.eissn | 2045-3701 | - |
dc.identifier.isi | WOS:000970093600001 | - |