Sterol-dependent nuclear import of ORP1S promotes LXR regulated trans-activation of apoE.
Oxysterol binding protein related protein 1S (ORP1S) is a member of a family of sterol transport proteins. Here we present evidence that ORP1S translocates from the cytoplasm to the nucleus in response to sterol binding. The sterols that best promote nuclear import of ORP1S also activate the liver X receptor (LXR) transcription factors and we show that ORP1S binds to LXRs, promotes binding of LXRs to LXR response elements (LXREs) and specifically enhances LXR-dependent transcription via the ME.1 and ME.2 enhancer elements of the apoE gene. We propose that ORP1S is a cytoplasmic sterol sensor, which transports sterols to the nucleus and promotes LXR-dependent gene transcription through select enhancer elements.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, United States. sungsoo.lee@utsouthwestern.edu
Sungsoo
S
Lee
Ping-Yuan
PY
Wang
Yangsik
Y
Jeong
David J
DJ
Mangelsdorf
Richard G W
RG
Anderson
Peter
P
Michaely
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000595:Amino Acid Sequence; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D000071518:Liver X Receptors; D008156:Luciferases; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013261:Sterols / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000098825:Oxysterol Binding Proteins
D001057:Apolipoproteins E; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011987:Receptors, Steroid; D013261:Sterols; D000098825:Oxysterol Binding Proteins; D008156:Luciferases