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 -deficient mice ( ), we observed that circadian rhythmicity of the metabolisms was phase-delayed. mice also exhibited other circadian abnormalities, including len...

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Bibliographic Details
Published in:eLife 2017-12, Vol.6
Main Authors: Hayasaka, Naoto, Hirano, Arisa, Miyoshi, Yuka, Tokuda, Isao T, Yoshitane, Hikari, Matsuda, Junichiro, Fukada, Yoshitaka
Format: Article
Language:English
Subjects:
Animals
Behavior
Behavior, Animal
Bioluminescence
Cell Line
Circadian Clocks
Circadian rhythm
Circadian rhythms
CLOCK protein
degradation
Entrainment
Experiments
Fibroblasts
Gene Expression Regulation
Humans
Kinases
knockout
Light effects
Liver
Metabolism
Mice
Mice, Knockout
Mutation
Neurons
Neuroscience
Neurosciences
PER2
Period 2 protein
Period Circadian Proteins - metabolism
Phosphatase
Phosphorylation
Phosphotransferases
Physiological research
Physiology
Protein Processing, Post-Translational
Protein-Serine-Threonine Kinases - deficiency
Protein-Serine-Threonine Kinases - metabolism
Proteins
Rodents
Salt-inducible kinase
SIK3
Suprachiasmatic nucleus
Synchronization
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Summary:Salt-inducible kinase 3 (SIK3) plays a crucial role in various aspects of metabolism. In the course of investigating metabolic defects in -deficient mice ( ), we observed that circadian rhythmicity of the metabolisms was phase-delayed. 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 vivo suprachiasmatic nucleus slices from mice exhibited destabilized and desynchronized molecular rhythms among individual neurons. In cultured cells, -knockdown resulted in abnormal bioluminescence rhythms. Expression levels of PER2, a clock protein, were elevated in -knockdown cells but down-regulated in -overexpressing cells, which could be attributed to a phosphorylation-dependent decrease in PER2 protein stability. This was further confirmed by PER2 accumulation in the fibroblasts and liver. Collectively, SIK3 plays key roles in circadian rhythms by facilitating phosphorylation-dependent PER2 destabilization, either directly or indirectly.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.24779