The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation

• Published in: Cell Vol. 161; no. 5; pp. 1138 - 1151
• Main Authors: Lipton, Jonathan O., Yuan, Elizabeth D., Boyle, Lara M., Ebrahimi-Fakhari, Darius, Kwiatkowski, Erica, Nathan, Ashwin, Güttler, Thomas, Davis, Fred, Asara, John M., Sahin, Mustafa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2015
• Subjects: Animals; ARNTL Transcription Factors - metabolism; Circadian Clocks; Cytosol - metabolism; Mice; Phosphorylation; Protein Biosynthesis; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.04.002

The circadian timing system synchronizes cellular function by coordinating rhythmic transcription via a transcription-translational feedback loop. How the circadian system regulates gene expression at the translational level remains a mystery. Here, we show that the key circadian transcription factor BMAL1 associates with the translational machinery in the cytosol and promotes protein synthesis. The mTOR-effector kinase, ribosomal S6 protein kinase 1 (S6K1), an important regulator of translation, rhythmically phosphorylates BMAL1 at an evolutionarily conserved site. S6K1-mediated phosphorylation is critical for BMAL1 to both associate with the translational machinery and stimulate protein synthesis. Protein synthesis rates demonstrate circadian oscillations dependent on BMAL1. Thus, in addition to its critical role in circadian transcription, BMAL1 is a translation factor that links circadian timing and the mTOR signaling pathway. More broadly, these results expand the role of the circadian clock to the regulation of protein synthesis. [Display omitted] •The circadian protein BMAL1 rhythmically interacts with the translational machinery•BMAL1 is a substrate of the mTOR-effector kinase S6K1•BMAL1 regulates circadian rhythms of protein synthesis BMAL1 rhythmically interacts with translational machinery, promoting protein synthesis in response to mTOR signaling. These findings connect circadian timing to the control of protein production.