Retinoic acid receptor-[alpha] regulates synthetic events in human platelets

• Published in: Journal of thrombosis and haemostasis 2017-12, Vol.15 (12), p.2408
• Main Authors: Schwertz, H, Rowley, J W, Zimmerman, G A, Weyrich, A S, Rondina, M T
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; Acids; Angiopoietin; Binding sites; Microtubule-associated protein 1; Platelets; Protein biosynthesis; Proteins; Retinoic acid; Retinoic acid receptors; Translation; Vitamin A
• ISSN: 1538-7933; 1538-7836
• DOI: 10.1111/jth.13861

Essentials Platelets express retinoic acid receptor (RAR)[alpha] protein, specifically binding target mRNAs. mRNAs under RAR[alpha] control include MAP1LC3B2, SLAIN2, and ANGPT1. All-trans retinoic acid (atRA) releases RAR[alpha] from its target mRNA. RAR[alpha] expressed in human platelets exerts translational control via direct mRNA binding. Summary Background Translational control mechanisms in platelets are incompletely defined. Here, we determined whether the nuclear transcription factor RAR[alpha] controls protein translational events in human platelets. Methods Isolated human platelets were treated with the pan-RAR agonist all-trans-retinoic acid (atRA). Global and targeted translational events were examined. Results Stimulation of platelets with atRA significantly increased global protein expression. RAR[alpha] protein bound to a subset of platelet mRNAs, as measured by next-generation RNA-sequencing. In-depth analyses of 5' and 3'-untranslated regions of the RAR[alpha]-bound mRNAs revealed consensus RAR[alpha] binding sites in microtubule-associated protein 1 light chain 3 beta 2 (MAP1LC3B2), SLAIN motif-containing protein 2 (SLAIN2) and angiopoietin-1 (ANGPT1) transcripts. When platelets were treated with atRA, binding interactions between RAR[alpha] protein and mRNA for MAP1LC3B2, SLAIN2 and ANGPT1 were significantly decreased. Consistent with the release of bound RAR[alpha] protein from MAP1LCB2mRNA, we observed an increase in the synthesis of MAP1LC3B2 protein. Conclusions These findings provide the first evidence that RAR[alpha], a nuclear transcriptional factor, regulates synthetic events in anucleate human platelets. They also reveal an additional non-genomic role for RAR[alpha] in platelets that may have implications for the vitamin A-dependent signaling in humans.