P54nrb/NONO regulates cAMP signaling and cortisol production by modulating phosphodiesterase splicing (1013.21)

Abstract

Phosphodiesterases (PDEs) play an integral role in modulating cellular signaling by degrading the second messenger cAMP. Mammalian PDEs are encoded by 21 different genes and are subdivided into 11 families (PDE1‐11), with more than 80 alternative splice variants generated from multiple promoters. We have shown previously that p54nrb/NONO is required for glucocorticoid biosynthesis, however the molecular mechanism by which p54nrb/NONO confers optimal cortisol production was unclear. We find that silencing p54nrb/NONO in H295R human adrenocortical cells abrogates adrenocorticotrophin (ACTH)‐stimulated cAMP production. Interestingly, the expression of multiple PDE isoforms, including PDE2, PDE3, PDE4, and PDE11 were induced in p54nrb/NONO knockdown cells. Analysis of PDE splice variants revealed that p54nrb/NONO plays a critical role in regulating PDE splicing. Additionally, whole transcriptome analysis identified that silencing p54nrb/NONO altered the splicing of multiple genes in adrenocortical cells, including cAMP responsive element binding protein 5 (CREB5), and histone deacetylase 9 (HDAC9). Collectively, our findings demonstrate that p54nrb/NONO plays a key role in regulating the capacity for cAMP signaling by controlling PDE splicing and expression, ultimately influencing glucocorticoid biosynthesis.Grant Funding Source: Supported by NIH GM073241.