Translational Regulation of Arylalkylamine N-acetyltransferase (AANAT) Synthesis by Heterogeneous Nuclear Ribonucleoprotein R (hnRNP R) in a Circadian Manner

Abstract

The daily on-time melatonin synthesis is necessary for the most of mammals on this planet, and arylalkylamine N-acetyltransferase (AANAT) is the core enzyme in melatonin production. Because melatonin participates in many physiological processes, rhythmic AANAT synthesis is a prominent circadian-controlled response that occurs in most mammals. In this research, my colleagues and I focused on the regulatory role of heterogeneous nuclear ribonucleoprotein R (hnRNP R) in the translation of AANAT. This novel RNA binding protein hnRNP R widely interacted with the 5’ untranslated region (UTR) of AANAT mRNA and contributed to translation through an internal ribosomal entry site (IRES). Fine-tuning of AANAT protein synthesis occurred in response to overexpression and downregulation of hnRNP R. Nocturnal elevation of AANAT protein was dependent on the rhythmic changes of hnRNP R, whose levels are elevated in the pineal gland during nighttime. Increases in hnRNP R additionally improved AANAT production in rat pinealocytes under norepinephrine (NE) treatment. These results suggest that cap-independent translation of AANAT mRNA plays a significant role in the rhythmic synthesis of melatonin through the recruitment of translational machinery to hnRNP R-bound AANAT mRNA.