Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1

Miriam Toledo, Ana Batista-Gonzalez, Emilio Merheb, Marie Louise Aoun, Elena Tarabra, Daorong Feng, Jaakko Sarparanta, Paola Merlo, Francesco Botrè, Gary J. Schwartz, Jeffrey E. Pessin, Rajat Singh

Research output: Contribution to journalArticlepeer-review

120 Scopus citations


The circadian clock coordinates behavioral and circadian cues with availability and utilization of nutrients. Proteasomal degradation of clock repressors, such as cryptochrome (CRY)1, maintains periodicity. Whether macroautophagy, a quality control pathway, degrades circadian proteins remains unknown. Here we show that circadian proteins BMAL1, CLOCK, REV-ERBα and CRY1 are lysosomal targets, and that macroautophagy affects the circadian clock by selectively degrading CRY1. Autophagic degradation of CRY1, an inhibitor of gluconeogenesis, occurs in a diurnal window when rodents rely on gluconeogenesis, suggesting that CRY1 degradation is time-imprinted to maintenance of blood glucose. High-fat feeding accelerates autophagic CRY1 degradation and contributes to obesity-associated hyperglycemia. CRY1 contains several light chain 3 (LC3)-interacting region (LIR) motifs, which facilitate the interaction of cargo proteins with the autophagosome marker LC3. Using mutational analyses, we identified two distinct LIRs on CRY1 that exert circadian glycemic control by regulating CRY1 degradation, revealing LIRs as potential targets for controlling hyperglycemia. Toledo et al. show that autophagy controls the liver clock by timely degradation of a circadian protein cryptochrome 1 (CRY1). CRY1 lowers glucose production in liver and its timely removal by autophagy allows glucose production. Obesity accentuates CRY1 degradation by autophagy, increasing glucose production and blood sugar levels.

Original languageEnglish
Pages (from-to)268-281.e4
JournalCell Metabolism
Issue number2
StatePublished - 7 Aug 2018
Externally publishedYes


  • CRY1
  • FoxO1
  • LC3
  • autophagy
  • circadian clock
  • gluconeogenesis
  • glucose metabolism
  • liver
  • lysosome
  • obesity


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