The NRON complex controls circadian clock function through regulated PER and CRY nuclear translocation

Yool Lee,Lauren J Francey,Andrew C Liu,John B Hogenesch,Chidambaram Ramanathan,Amita Sehgal,Yang Shen

doi:10.1038/s41598-019-48341-8

Abstract

Post-translational regulation plays a central role in the circadian clock mechanism. However, nucleocytoplasmic translocation of core clock proteins, a key step in circadian timekeeping, is not fully understood. Earlier we found that the NRON scaffolding complex regulates nuclear translocation of NFAT and its signaling. Here, we show that components of the NRON complex also regulate the circadian clock. In peripheral cell clock models, genetic perturbation of the NRON complex affects PER and CRY protein nuclear translocation, dampens amplitude, and alters period length. Further, we show small molecules targeting the NFAT pathway alter nuclear translocation of PER and CRY proteins and impact circadian rhythms in peripheral cells and tissue explants of the master clock in the suprachiasmatic nucleus. Taken together, these studies highlight a key role for the NRON complex in regulating PER/CRY subcellular localization and circadian timekeeping.

Highlights

Most organisms evolved endogenous circadian clocks that control ~24 h rhythms in physiology
Previous studies including ours show that several components of the NRON complex, including CSNK1E, GSK3B, and DYRK1A, regulate clock function in mammals[13,21,22]
This phenotypic difference may reflect cell line or type-specific clock function. These results suggest that the NRON complex, known for its role in regulating NFAT signaling, regulates the circadian clock

Summary

Introduction

Most organisms evolved endogenous circadian clocks that control ~24 h rhythms in physiology. Www.nature.com/scientificreports assembly of a large RNA/protein complex, consisting of three distinct, functionally interrelated groups of protein components, namely the NRON complex[23,27] (Fig. 1A): (1) kinases (CSNK1E, GSK3B, DYRK1A), phosphatases (PP2A, calcineurin (or PP2B), PPP2R1A), and scaffolding proteins (IQGAP1) are involved in signal transduction and post-translational modifications; (2) EIF3E, CUL4B, PSMD11, and HUWE1, of which PSMD11 and CUL4B are proteasome components, regulate protein synthesis and turnover; and (3) CSE1L, KPNB1 and TNPO1 participate in nucleocytoplasmic transport. The kinases in the complex (CSNK1E, GSK3B, DYRK1A) were shown to regulate NFAT function[10,27,28] These kinases regulate phosphorylation-related proteolysis and nuclear entry of PER and CRY proteins[13,14,20,22]. The NFAT and circadian clock pathways share functional components

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Conclusion