Nuclear Receptor Ligand Is a Gas

Abstract

Nuclear receptors function as ligand-regulated transcription factors, but for many family members the ligands remain unknown. Before the fine piece of detective work reported by Reinking et al. , only one of the 18 nuclear receptor proteins in Drosophila had an identified ligand. The clue that broke open the case and allowed the authors to find an unexpected partner for the receptor known as E75 was the blood-red color of the purified protein. Electron absorption and mass spectrometry analysis revealed that the receptor has a tightly associated heme group. Further analysis led the authors to propose three possible functions of the receptor complex. First, heme was required for stability of the E75 protein, and thus E75 could serve as a sensor of cellular heme concentration. Heme-containing proteins are well known to bind gases, and E75 is no exception. Binding of CO or NO to E75 was detected spectrophotometrically, and denaturation assays showed that CO binding stabilized the protein. E75 interacts with another nuclear receptor, HR3, and inhibits activation of target genes by HR3. CO binding inhibited interaction of a peptide from HR3 with E75. Functionally, treatment of cells with NO donors relieved inhibitory effects of E75 on HR3-induced transcription. Thus, a second possibility is that E75 senses CO and NO as intracellular signaling molecules. Finally, E75 might also serve as a redox sensor because only the reduced form of E75 was stabilized by interaction with the HR3 peptide. The authors (and commentator Thummel) discuss a range of biological processes--from development and metabolism to circadian timing--that are potential targets of regulation by E75. J. Reinking, M. Lam, K. Pardee, H. Sampson, S. Liu, P. Yang, S. Williams, W. White, G. Lajoie, A. Edwards, The nuclear receptor E75 contains heme and is gas responsive. Cell 122 , 195-207 (2005). [PubMed] C. Thummel, Powered by gas: A ligand for a fruit fly nuclear receptor. Cell 122 , 151-153 (2005). [PubMed]