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J Steroid Biochem Mol Biol. 2018 Nov;184:11-19. doi: 10.1016/j.jsbmb.2018.06.014. Epub 2018 Jun 22.

NR3E receptors in cnidarians: A new family of steroid receptor relatives extends the possible mechanisms for ligand binding.

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Marine Genomics Unit, Okinawa Institute of Science and Technology, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan.
Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), Illkirch, France; Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France; Université de Strasbourg, Strasbourg, France.
Department of Biological Sciences, University of North Carolina, Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA.
Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543, USA.
Sorbonne Université, CNRS, Observatoire océanologique de Banyuls-sur-mer, Avenue de Fontaule, 66650 Banyuls-sur-mer, France.
Sorbonne Université, CNRS, UMR 8227 Integrative Biology of Marine Models, Station Biologique de Roscoff, Place Georges Teissier, CS 90074, 29688 Roscoff Cedex, France. Electronic address:


Steroid hormone receptors are important regulators of development and physiology in bilaterian animals, but the role of steroid signaling in cnidarians has been contentious. Cnidarians produce steroids, including A-ring aromatic steroids with a side-chain, but these are probably made through pathways different than the one used by vertebrates to make their A-ring aromatic steroids. Here we present comparative genomic analyses indicating the presence of a previously undescribed nuclear receptor family within medusozoan cnidarians, that we propose to call NR3E. This family predates the diversification of ERR/ER/SR in bilaterians, indicating that the first NR3 evolved in the common ancestor of the placozoan and cnidarian-bilaterian with lineage-specific loss in the anthozoans, even though multiple species in this lineage have been shown to produce aromatic steroids, whose function remain unclear. We discovered serendipitously that a cytoplasmic factor within epidermal cells of transgenic Hydra vulgaris can trigger the nuclear translocation of heterologously expressed human ERα. This led us to hypothesize that aromatic steroids may also be present in the medusozoan cnidarian lineage, which includes Hydra, and may explain the translocation of human ERα. Docking experiments with paraestrol A, a cnidarian A-ring aromatic steroid, into the ligand-binding pocket of Hydra NR3E indicates that, if an aromatic steroid is indeed the true ligand, which remains to be demonstrated, it would bind to the pocket through a partially distinct mechanism from the manner in which estradiol binds to vertebrate ER.


A-ring aromatic steroid; Aromatization; Cnidarian; Steroid receptor

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