Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein
Salt-inducible kinase 3 (SIK3) plays a crucial role in various aspects of metabolism. In the course of investigating metabolic defects in Sik3-deficient mice (Sik3-/-), we observed that circadian rhythmicity of the metabolisms was phase-delayed. Sik3-/- mice also exhibited other circadian abnormalities, including lengthening of the period, impaired entrainment to the light-dark cycle, phase variation in locomotor activities, and aberrant physiological rhythms. Ex vivosuprachiasmatic nucleus slices from Sik3-/- mice exhibited destabilized and desynchronized molecular rhythms among individual neurons. In cultured cells, Sik3-knockdown resulted in abnormal bioluminescence rhythms. Expression levels of PER2, a clock protein, were elevated in Sik3-knockdown cells but down-regulated in Sik3-overexpressing cells, which could be attributed to a phosphorylation-dependent decrease in PER2 protein stability. This was further confirmed by PER2 accumulation in the Sik3-/- fibroblasts and liver. Collectively, SIK3 plays key roles in circadian rhythms by facilitating phosphorylation-dependent PER2 destabilization, either directly or indirectly.
Article and author information
Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research 25293053)
- Naoto Hayasaka
Japan Science and Technology Agency (PRESTO)
- Naoto Hayasaka
Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research 24227001)
- Yoshitaka Fukada
Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research 17H06096)
- Yoshitaka Fukada
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Japan Society for Promotion of Sciences. All of the animals were handled according to approved institutional animal care and use committees of Kindai University (KAME- 19-051) and Nagoya University (17239).
- Jeff Price
- Received: January 2, 2017
- Accepted: December 8, 2017
- Accepted Manuscript published: December 11, 2017 (version 1)
- Version of Record published: December 29, 2017 (version 2)
- Version of Record updated: January 10, 2018 (version 3)
- Version of Record updated: January 25, 2021 (version 4)
© 2017, Hayasaka et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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