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

Hayasaka, N.

doi:10.1101/124354

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bioRxiv · 10.1101/124354

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

Hayasaka, N.

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Abstract

Salt-inducible kinase 3 (SIK3) plays a crucial role in various aspects of metabolism, as well as in skeletal development. In the course of investigating metabolic defects in the Sik3-deficient mice (Sik3-/-), we observed that circadian rhythmicity of the metabolisms was phase-delayed. Sik3-/- mice also displayed other abnormalities in circadian rhythms, 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 cycle-to-cycle fluctuations of the circadian periodicity. Expression levels of PER2, an essential clock protein, were elevated in Sik3-knockdown cells but down-regulated in Sik3-overexpressing cells, which could be ascribed to a phosphorylation-dependent decrease in PER2 protein stability. Collectively, our results indicate that SIK3 plays key roles in murine circadian rhythms by facilitating phosphorylation-dependent destabilization of PER2.

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Hayasaka, N.. 2017-04-05. Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein. https://doi.org/10.1101/124354

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