AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation.
Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.
Lamia
Katja A
KA
Gene Expression Laboratory, the Salk Institute, La Jolla, CA 92037, USA.
Sachdeva
Uma M
UM
DiTacchio
Luciano
L
Williams
Elliot C
EC
Alvarez
Jacqueline G
JG
Egan
Daniel F
DF
Vasquez
Debbie S
DS
Juguilon
Henry
H
Panda
Satchidananda
S
Shaw
Reuben J
RJ
Thompson
Craig B
CB
Evans
Ronald M
RM
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D056930:ARNTL Transcription Factors; D019943:Amino Acid Substitution; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes; D003470:Culture Media; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D005502:Food; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction
D055372:AMP-Activated Protein Kinases; D056930:ARNTL Transcription Factors; D000620:Aminoimidazole Carboxamide; D051792:Basic Helix-Loop-Helix Proteins; D056931:Cryptochromes; D003470:Culture Media; D005420:Flavoproteins; D005947:Glucose; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; D012265:Ribonucleotides; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C538963:CRY1 protein, human; C538964:Cry1 protein, mouse; C031143:AICA ribonucleotide