SAT-LB063 The ZFP36 Family of RNA-Binding Proteins Regulate Human Steroidogenesis

Human steroid hormones produced by the adrenal cortex control important physiology including metabolism, inflammation, blood pressure and volume, and sexual characteristics. While the signaling components, transcriptional regulators, and steroidogenic enzymes necessary for adrenocortical production of hormones have been identified, little to nothing is known about post-transcriptional regulation by RNA-binding proteins (RBPs). Recently technological advances have revolutionized our ability to investigate RBP-driven RNA regulation making it possible for the first time to investigate how this mechanism controls steroidogenesis. We have recently carried out an siRNA screen of RBPs regulating human aldosterone production that revealed a critical role for the tristetraprolin (ZFP36) family of RNA-binding protein. The ZFP36 family of RBPs binds to AU-rich elements in 3’UTRs and consequently destabilizes and/or translationally represses these ARE-containing mRNAs. Remarkably, depletion of either ZFP36L2 or ZFP36L1 significantly increased aldosterone levels. In addition, we have data demonstrating that: 1) mRNA stability controls the temporal pattern of RNA expression during steroidogenesis; 2) mRNAs with AU-rich elements (AREs) in their 3’ UTR are rapidly induced and cleared out in response to steroidogenic stimulation; 3) The ZFP36 family of RBPs are induced during steroidogenesis. We propose a model in which the ZFP36 family of proteins operate a negative feedback loop that prevent overproduction of aldosterone by destabilizing and/or translationally repressing ARE-containing mRNAs encoding steroidogenic proteins. Notably, over-production of aldosterone is a major cause of hypertension, suggesting that failure of this negative feedback loop could have important implications for human health. Our ongoing work will elucidate the mechanism underlying this negative feedback loop that controls aldosterone biosynthesis post-transcriptionally through the action of ZFP36 RNA binding proteins and yet to be discovered factors that they interact with. The adrenal cortex is amenable to the delivery of modified antisense oligonucleotides. Thus, our discoveries can facilitate the design of oligonucleotide therapeutics that can be used to precisely and specifically modulate human steroidogenesis. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.