Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1

Cell Metab. 2018 Aug 7;28(2):268-281.e4. doi: 10.1016/j.cmet.2018.05.023. Epub 2018 Jun 21.

Abstract

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.

Keywords: CRY1; FoxO1; LC3; autophagy; circadian clock; gluconeogenesis; glucose metabolism; liver; lysosome; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / metabolism
  • Animals
  • Autophagy*
  • CLOCK Proteins / metabolism
  • Circadian Clocks*
  • Circadian Rhythm
  • Cryptochromes / metabolism*
  • Diet, High-Fat / methods
  • Gluconeogenesis
  • Glucose / metabolism*
  • Hyperglycemia / metabolism*
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Proteolysis

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Cry1 protein, mouse
  • Cryptochromes
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • CLOCK Proteins
  • Clock protein, mouse
  • Glucose