Nuclear Receptor Rev-Erbα: A Heme Receptor that Coordinates Circadian Rhythm and Metabolism

Abstract

Nuclear receptor Rev-erbα (NR1D1), previously considered to be an orphan nuclear receptor, is a receptor for heme, which promotes transcriptional repression via recruitment of the NCoR-HDAC3 corepressor complex. Rev-erbα gene regulation is circadian, and Rev-erbα comprises a critical negative limb of the core circadian clock by directly repressing the expression of the positive clock component, Bmal1. Rev-erbα also regulates the metabolic gene pathway, thus serving as a heme sensor for coordination of circadian and metabolic pathways.

Structure of REV-ERBβ Ligand-binding Domain Bound to a Porphyrin Antagonist

“…Thus, REV-ERBs were thought to be constitutive repressors of transcription based on their ability to recruit corepressor proteins and suppress target gene transcription. Recently, we and others identified the porphyrin heme as a physiological agonist for both REV-ERBs (4,10). Heme binds directly to the REV-ERB ligand-binding domain (LBD) and regulates the ability of REVERBs to recruit NR corepressors such as NCoR to target gene promoters and repress transcription of downstream genes (4,10).…”

“…Recently, we and others identified the porphyrin heme as a physiological agonist for both REV-ERBs (4,10). Heme binds directly to the REV-ERB ligand-binding domain (LBD) and regulates the ability of REVERBs to recruit NR corepressors such as NCoR to target gene promoters and repress transcription of downstream genes (4,10). A crystal structure of heme bound within the ligand-binding pocket of REV-ERB␤ has also been described confirming these biological observations (11).…”

“…The nuclear receptors (NRs) 6 REV-ERB␣ and REV-ERB␤ regulate a number of physiological functions including circadian rhythm, lipid metabolism, cellular differentiation, and muscle endurance (1)(2)(3)(4)(5). The REV-ERBs were originally identified as orphan receptors due to the lack of an identifiable physiological ligand (6,7).…”

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…CORMs (tricarbonyldichl ororuthenium(ii) dimer; [Ru(CO) 3 Cl 2 ] 2 ) or iCORMs (ruthenium(iii) chloride; RuCl 3 ) were purchased from Sigma-Aldrich and dissolved in a mixture of DMSO and ethanol. 1 mol CORMs dissociates into 4 mol CO. We used 400 M CO in these experiments, a concentration eight times higher than 6% CO (50 M); however, in contrast to that from constant gas treatment, CO from CORMs volatizes very rapidly, and only an undefined concentration reaches the cells.…”

Avian central clocking system

“…Molekularny mechanizm pracy oscylatora został opracowany na podstawie badań nad modelami cyjanobakterii, grzybów Neurospora, muszki owocówki i myszy, wykazując, że struktura funkcjonowania oscylatora jest uniwersalna w całym świecie zwierzęcym (16,30,42,50,100). Dotychczas w CCS ptaków zidentyfikowano geny zegarowe: Bmal1, Bmal2, Clock, NPas2 zwany też Mop4 i Rorα -stanowiące pozytywny element systemu kodujący białkowe aktywatory transkrypcyjne; oraz Cry1, Cry2, Per2, Per3, E4bp4 i Rev-erbα -tworzące negatywny element systemu kodujący represory transkrypcji (2,21,28,69,87,93,(96)(97)(98). U ssaków dodatkowo występuje Per1, a u kury i wróbla domowego zidentyfikowano nowy Cry4, który jest homologiem Cry4 u ryb (35,43,50,98).…”