Abstract
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, LXRβ directly binds to the C-terminal region ((2247)LTSFL(2251)) of ABCA1 to mediate its post-translational regulation. In the absence of cholesterol accumulation in the macrophage-like cell line THP-1, the ABCA1-LXRβ 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 LXRβ to dissociate from ABCA1, thus freeing ABCA1 for apoA-I binding and subsequent cholesterol efflux. Photoaffinity labeling experiments with 8-azido-[α-(32)P]ATP showed that the interaction of LXRβ 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. LXRβ can cause a post-translational response by binding directly to ABCA1, as well as a transcriptional response, to maintain cholesterol homeostasis.
Highlights
Disruption of cellular cholesterol homeostasis can lead to a variety of pathological conditions, including cardiovascular disease [1]
We showed that liver X receptor (LXR) interacts directly with ATP-binding cassette protein A1 (ABCA1) and that the interaction with ABCA1 recruits LXR in the vicinity of the plasma membrane in the absence of LXR ligands, i.e. when cholesterol is not in excess in cells
LXR interaction blocks apolipoprotein A-I (apoA-I) binding to ABCA1 and cholesterol loading by ABCA1 onto apoA-I, keeping ABCA1 standby on the plasma membrane
Summary
Disruption of cellular cholesterol homeostasis can lead to a variety of pathological conditions, including cardiovascular disease [1]. In the absence of cholesterol accumulation in the macrophage-like cell line THP-1, the ABCA1-LXR complex stably localizes to the plasma membrane, but apolipoprotein A-I (apoA-I) binding or cholesterol efflux does not occur.
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