Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein

  1. Naoto Hayasaka  Is a corresponding author
  2. Arisa Hirano
  3. Yuka Miyoshi
  4. Isao T Tokuda
  5. Hikari Yoshitane
  6. Junichiro Matsuda
  7. Yoshitaka Fukada
  1. Nagoya University, Japan
  2. The University of Tokyo, Japan
  3. Kindai University, Japan
  4. Ritsumeikan University, Japan
  5. National Institutes of Biomedical Innovation, Health and Nutrition, Japan

Abstract

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

Author details

  1. Naoto Hayasaka

    Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
    For correspondence
    naotohayasaka@yahoo.co.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2844-524X
  2. Arisa Hirano

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuka Miyoshi

    Department of Anatomy and Neurobiology, Kindai University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Isao T Tokuda

    Department of Mechanical Engineering, Ritsumeikan University, Kusatsu, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6212-0022
  5. Hikari Yoshitane

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Junichiro Matsuda

    Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Yoshitaka Fukada

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

Funding

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.

Ethics

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).

Reviewing Editor

  1. Jeff Price

Publication history

  1. Received: January 2, 2017
  2. Accepted: December 8, 2017
  3. Accepted Manuscript published: December 11, 2017 (version 1)
  4. Version of Record published: December 29, 2017 (version 2)
  5. Version of Record updated: January 10, 2018 (version 3)
  6. Version of Record updated: January 25, 2021 (version 4)

Copyright

© 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.

Metrics

  • 4,043
    Page views
  • 627
    Downloads
  • 20
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Naoto Hayasaka
  2. Arisa Hirano
  3. Yuka Miyoshi
  4. Isao T Tokuda
  5. Hikari Yoshitane
  6. Junichiro Matsuda
  7. Yoshitaka Fukada
(2017)
Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein
eLife 6:e24779.
https://doi.org/10.7554/eLife.24779

Further reading

    1. Neuroscience
    2. Physics of Living Systems
    Sabrina A Jones, Jacob H Barfield ... Woodrow L Shew
    Research Article

    Naturally occurring body movements and collective neural activity both exhibit complex dynamics, often with scale-free, fractal spatiotemporal structure. Scale-free dynamics of both brain and behavior are important because each is associated with functional benefits to the organism. Despite their similarities, scale-free brain activity and scale-free behavior have been studied separately, without a unified explanation. Here we show that scale-free dynamics of mouse behavior and neurons in visual cortex are strongly related. Surprisingly, the scale-free neural activity is limited to specific subsets of neurons, and these scale-free subsets exhibit stochastic winner-take-all competition with other neural subsets. This observation is inconsistent with prevailing theories of scale-free dynamics in neural systems, which stem from the criticality hypothesis. We develop a computational model which incorporates known cell-type-specific circuit structure, explaining our findings with a new type of critical dynamics. Our results establish neural underpinnings of scale-free behavior and clear behavioral relevance of scale-free neural activity.