regulation of bmal1 protein stability and circadian function by gsk3β-mediated phosphorylation监管bmal1 gsk3β-mediated磷酸化蛋白质稳定性和生理功能.pdfVIP

Regulation of BMAL1 Protein Stability and Circadian Function by GSK3b-Mediated Phosphorylation 1,3 1 2 2,3 1,3 Saurabh Sahar , Loredana Zocchi , Chisato Kinoshita , Emiliana Borrelli , Paolo Sassone-Corsi * 1 Department of Pharmacology, University of California Irvine, Irvine, California, United States of America, 2 Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, California, United States of America, 3 Unite 904 INSERM ‘Epigenetics and Neuronal Plasticity’, University of California Irvine, Irvine, California, United States of America Abstract Background: Circadian rhythms govern a large array of physiological and metabolic functions. To achieve plasticity in circadian regulation, proteins constituting the molecular clock machinery undergo various post-translational modifications (PTMs), which influence their activity and intracellular localization. The core clock protein BMAL1 undergoes several PTMs. Here we report that the Akt-GSK3b signaling pathway regulates BMAL1 protein stability and activity. Principal Findings: GSK3b phosphorylates BMAL1 specifically on Ser 17 and Thr 21 and primes it for ubiquitylation. In the absence of GSK3b-mediated phosphorylation, BMAL1 becomes stabilized and BMAL1 dependent circadian gene expression is dampened. Dopamine D2 receptor mediated signaling, known to control the Akt-GSK3b pathway, influences BMAL1 stability and in vivo circadian gene expression in striatal neurons. Conclusions: These findings uncover a previously unknown mechanism of circadian clock control. The GSK3 b kinase phosphorylates BMAL1, an event that controls the stability of