Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta.
The nuclear receptors REV-ERBalpha (encoded by NR1D1) and REV-ERBbeta (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.
Department of Pharmacology and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0733, USA.
Srilatha
S
Raghuram
Keith R
KR
Stayrook
Pengxiang
P
Huang
Pamela M
PM
Rogers
Amanda K
AK
Nosie
Don B
DB
McClure
Lorri L
LL
Burris
Sepideh
S
Khorasanizadeh
Thomas P
TP
Burris
Fraydoon
F
Rastinejad
D002460:Cell Line; D002942:Circular Dichroism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006418:Heme / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008024:Ligands; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008024:Ligands; C064353:NR1D1 protein, human; C090977:NR1D2 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D006418:Heme