Abstract
Nuclear receptors (NRs) are transcription factors accomplishing a multiplicity of functions, essential for organismal homeostasis. Among their numerous members, the retinoid X receptor (RXR) is a central player of the endocrine system, with a singular ability to operate as a homodimer or a heterodimer with other NRs. Additionally, RXR has been found to be a critical actor in various processes of endocrine disruption resulting from the exposure to a known class of xenobiotics termed organotins (e.g., tributyltin (TBT)), including imposex in gastropod molluscs and lipid perturbation across different metazoan lineages. Thus, given its prominent physiological and endocrine role, RXR is present in the genomes of most extant metazoan species examined to date. Here, we expand on the phylogenetic distribution of RXR across the metazoan tree of life by exploring multiple next-generation sequencing projects of protostome lineages. By addressing amino acid residue conservation in combination with cell-based functional assays, we show that RXR induction by 9-cis retinoic acid (9cisRA) and TBT is conserved in more phyla than previously described. Yet, our results highlight distinct activation efficacies and alternative modes of RXR exploitation by the organotin TBT, emphasizing the need for broader species sampling to clarify the mechanistic activation of RXR.
Highlights
Nuclear receptors (NRs) constitute an exceptionally vast family of metazoan transcription factors [1,2]
Bugula neritina specimens were collected at the Marina da Póvoa de Varzim, Portugal; Phoronopsis californica, and Megathiris detruncata specimens were collected at Madeira Island, Portugal; Bonellia viridis was sampled at Peniche, Portugal; Priapulus caudatus and Xenoturbella bocki specimens were collected at the Gullmarn fjord, Sweden
We investigated a set of currently available genomes and transcriptomes from multiple metazoan phyla to retrieve partial retinoid X receptor (RXR) amino acid sequences
Summary
Nuclear receptors (NRs) constitute an exceptionally vast family of metazoan transcription factors [1,2]. RXR, for instance, is activated by small lipophilic molecules, including the high-affinity ligand 9-cis retinoic acid (9cisRA) [21]. This canonical high affinity activity has been corroborated in various lineages such as vertebrates, molluscs, and annelids [22,23,24,25,26,27,28]. Low amounts of endogenous 9cisRA are usually detected in animal tissues, and this is further hampered by the instability of RA isomers [34] Other molecules, such as polyunsaturated fatty acids (PUFAs), were suggested to act as natural ligand of RXR [35,36]. The full set of endogenous RXR ligands remains to be fully determined [21,37]
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