title: The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation.
abstract: 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.
authors.affiliation: Department of Neurology, Kirby Neurobiology Center, Children's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Lipton
authors.affiliation: Department of Neurology, Kirby Neurobiology Center, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Yuan
authors.affiliation: Department of Neurology, Kirby Neurobiology Center, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Lara M
authors.initials: LM
authors.lastname: Boyle
authors.affiliation: Department of Neurology, Kirby Neurobiology Center, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Darius
authors.initials: D
authors.lastname: Ebrahimi-Fakhari
authors.affiliation: Department of Neurology, Kirby Neurobiology Center, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Kwiatkowski
authors.affiliation: Department of Neurology, Kirby Neurobiology Center, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Nathan
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Güttler
authors.affiliation: Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Davis
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Neurology, Kirby Neurobiology Center, Children's Hospital, Boston, MA 02115, USA. Electronic address: mustafa.sahin@childrens.harvard.edu.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D057906:Circadian Clocks; D003600:Cytosol / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases