Format

Send to

Choose Destination
Sci Rep. 2019 Aug 15;9(1):11883. doi: 10.1038/s41598-019-48341-8.

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

Author information

1
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
2
Penn Chronobiology, Howard Hughes Medical Institute, Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
3
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, 32610, USA.
4
Department of Biological Sciences, University of Memphis, Memphis, TN, 38152, USA.
5
Divisions of Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
6
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. john.hogenesch@cchmc.org.
7
Divisions of Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA. john.hogenesch@cchmc.org.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center