Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ

被引:466
作者
Raghuram, Srilatha
Stayrook, Keith R.
Huang, Pengxiang
Rogers, Pamela M.
Nosie, Amanda K.
McClure, Don B.
Burris, Lorri L.
Khorasanizadeh, Sepideh
Burris, Thomas P.
Rastinejad, Fraydoon
机构
[1] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nucl Receptor Lab, Baton Rouge, LA 70808 USA
[2] Univ Virginia Hlth Syst, Dept Pharmacol, Charlottesville, VA 22908 USA
[3] Univ Virginia Hlth Syst, Ctr Mol Design, Charlottesville, VA 22908 USA
[4] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
[5] Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA
关键词
D O I
10.1038/nsmb1344
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The nuclear receptors REV-ERB alpha (encoded by NR1D1) and REV-ERB beta (NR1D2) have remained orphans owing to the lack of identified physiological ligands. Here we show that heme is a physiological ligand of both receptors. Heme associates with the ligand-binding domains of the REV-ERB receptors with a 1: 1 stoichiometry and enhances the thermal stability of the proteins. Results from experiments of heme depletion in mammalian cells indicate that heme binding to REV-ERB causes the recruitment of the co-repressor NCoR, leading to repression of target genes including BMAL1 (official symbol ARNTL), an essential component of the circadian oscillator. Heme extends the known types of ligands used by the human nuclear receptor family beyond the endocrine hormones and dietary lipids described so far. Our results further indicate that heme regulation of REV-ERBs may link the control of metabolism and the mammalian clock.
引用
收藏
页码:1207 / 1213
页数:7
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