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

eLife

Yuka Miyoshi¹  Arisa Hirano²  Hikari Yoshitane³  Yoshitaka Fukada⁴  Isao T Tokuda⁴  Junichiro Matsuda⁵  Naoto Hayasaka⁶ 

[1] Department of Anatomy and Neurobiology, Kindai University Faculty of Medicine, Osaka, Japan;PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan;Department of Anatomy and Neurobiology, Kindai University Faculty of Medicine, Osaka, Japan;Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo, Japan;Department of Mechanical Engineering, Ritsumeikan University, Kusatsu, Japan;Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan;

关键词: SIK3;    knockout;    circadian rhythm;    PER2;    degradation;    salt-inducible kinase;   

DOI  :  10.7554/eLife.24779

来源: DOAJ

【 摘 要 】

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 vivo suprachiasmatic 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.

【 授权许可】

Unknown