Heterogeneous ribonucleoprotein R regulates arylalkylamine N‐acetyltransferase synthesis via internal ribosomal entry site‐mediated translation in a circadian manner

Abstract

Rhythmic arylalkylamine N-acetyltransferase (AANAT) synthesis is a prominent circadian-controlled response that occurs in most mammals. AANAT is the core enzyme in melatonin production; because melatonin participates in many physiological processes, the regulation of AANAT is an important research topic. In this study, we focused on the role of heterogeneous ribonucleoprotein R (hnRNP R) in the translation of AANAT. A 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 knockdown and overexpression 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 role in the rhythmic synthesis of melatonin through the recruitment of translational machinery to hnRNP R-bound AANAT mRNA.

Heterogeneous nuclear ribonucleoprotein A1 regulates rhythmic synthesis of mouse Nfil3 protein via IRES-mediated translation

“…During IRES-mediated regulation, ribosomes are recruited directly to the 5′-UTR to process translation in a cap-independent manner 29 . Moreover, previous studies have suggested that cellular IRES-mediated translation occurs under specific stress conditions 30 31 32 and is required for robust oscillation of clock proteins 33 34 35 , which consolidates our suggested mechanisms.…”

The hnRNP family: insights into their role in health and disease

“…The presence of the above-mentioned RBDs suggests additional post-transcriptional roles. More importantly, hnRNP R is also found in the cytosol where it regulates cap-independent translation by binding to the IRES of target mRNAs (Lee et al 2015 ).…”

Role of AA-NAT and TPH1 in the Ghrelin-Dependent Regulation of Melatonin Secretion in Sheep during Different Seasons: An <em>In Vitro</em> Study

“…However, the most attention has been paid to the species-specific regulation of AA-NAT synthesis. The nocturnal elevation of AA-NAT activity is dependent on AA-NAT gene transcription [38] and the role of the RNA-binding protein heterogeneous ribonucleoprotein R (hnRNP R) in the translation of AA-NAT in rats [39]. However, in sheep [14,19,20], cattle [21] and humans [14], it mainly depends on changes in AA-NAT phosphorylation and post-translational modifications of the AA-NAT protein, such as proteasomal degradation.…”