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. 2020 Aug 26;11:4265. doi: 10.1038/s41467-020-18042-2

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — Retinoid chemical structures (a) and RA signaling pathway (b). Blood-circulating retinol is internalized through membrane transporter and receptor stimulated by retinoic acid 6 (STRA6) and converted into all-trans retinoic acid (RA), which binds to cellular retinoic acid-binding protein type 2 for signaling in the nucleus. RA triggers gene transcription by binding to RA receptors (RAR) and to the retinoid X receptor (RXR). In the presence of the ligand, RAR and RXR heterodimerize on retinoic acid-response element (RARE) sequences located in promoter regions inducing the transcription of target genes. Of note, RXR may also homodimerize and trigger gene transcription (not depicted in the illustration). RA signaling may also occur via activation of receptors associated with lipid rafts located on the cell surface, which trigger transcriptional activation of target genes by histone and receptor phosphorylation in the cell nucleus. ADH alcohol dehydrogenase, CRBP cellular retinol-binding protein 1, CYP26 cytochrome P450 family 26, Gαq Gq protein alpha subunit, MAPK mitogen activated protein kinases, P phosphorylation, RALDH retinaldehyde dehydrogenase, RBP4 retinol-binding protein 4, RDH retinol dehydrogenase.