Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 22, Pages 20117-20124Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.235846
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Program for Promotion of Basic and Applied Researches for Innovations in Bio-oriented Industry (BRAIN) of Japan
- Takeda Scientific Foundation
- World Premier International Research Center Initiative, MEXT, Japan
- Grants-in-Aid for Scientific Research [20380186, 20228001] Funding Source: KAKEN
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Cells have evolved multiple mechanisms for maintaining cholesterol homeostasis, and, among these, ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux is highly regulated at the transcriptional level through the activity of the nuclear receptor liver X receptor (LXR). Here, we show that in addition to its well defined role in transcription, LXR beta directly binds to the C-terminal region ((LTSFL2251)-L-2247) of ABCA1 to mediate its post-translational regulation. In the absence of cholesterol accumulation in the macrophage-like cell line THP-1, the ABCA1-LXR beta complex stably localizes to the plasma membrane, but apolipoprotein A-I (apoA-I) binding or cholesterol efflux does not occur. Exogenously added LXR ligands, which mimic cholesterol accumulation, cause LXR beta to dissociate from ABCA1, thus freeing ABCA1 for apoA-I binding and subsequent cholesterol efflux. Photoaffinity labeling experiments with 8-azido-[alpha-P-32] ATP showed that the interaction of LXR beta with ABCA1 inhibits ATP binding by ABCA1. This is the first study to show that a protein-protein interaction with the endogenous protein suppresses the function of ABC proteins by inhibiting ATP binding. LXR beta can cause a post-translational response by binding directly to ABCA1, as well as a transcriptional response, to maintain cholesterol homeostasis.
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