Regulation of BMAL1 protein stability and circadian function by GSK3beta-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-GSK3beta signaling pathway regulates BMAL1 protein stability and activity.


RESULTS
GSK3beta phosphorylates BMAL1 specifically on Ser 17 and Thr 21 and primes it for ubiquitylation. In the absence of GSK3beta-mediated phosphorylation, BMAL1 becomes stabilized and BMAL1 dependent circadian gene expression is dampened. Dopamine D2 receptor mediated signaling, known to control the Akt-GSK3beta 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 GSK3beta 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.
Sahar
Saurabh
S
Department of Pharmacology, University of California Irvine, Irvine, California, United States of America.
Zocchi
Loredana
L
Kinoshita
Chisato
C
Borrelli
Emiliana
E
Sassone-Corsi
Paolo
P
D056930:ARNTL Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002940:Circadian Rhythm; D004298:Dopamine / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D054875:Ubiquitination
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D012333:RNA, Messenger; D013912:Threonine; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine