Regulation of BMAL1 Protein Stability and Circadian Function by GSK3 beta-Mediated Phosphorylation

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-GSK3 beta signaling pathway regulates BMAL1 protein stability and activity. Principal Findings: GSK3 beta phosphorylates BMAL1 specifically on Ser 17 and Thr 21 and primes it for ubiquitylation. In the absence of GSK3 beta-mediated phosphorylation, BMAL1 becomes stabilized and BMAL1 dependent circadian gene expression is dampened. Dopamine D2 receptor mediated signaling, known to control the Akt-GSK3 beta 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 beta kinase phosphorylates BMAL1, an event that controls the stability of the protein and the amplitude of circadian oscillation. BMAL1 phosphorylation appears to be an important regulatory step in maintaining the robustness of the circadian clock.