Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1

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 unknow...

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Veröffentlicht in:Cell metabolism 2018-08, Vol.28 (2), p.268-281.e4
Hauptverfasser: Toledo, Miriam, Batista-Gonzalez, Ana, Merheb, Emilio, Aoun, Marie Louise, Tarabra, Elena, Feng, Daorong, Sarparanta, Jaakko, Merlo, Paola, Botrè, Francesco, Schwartz, Gary J., Pessin, Jeffrey E., Singh, Rajat
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container_end_page 281.e4
container_issue 2
container_start_page 268
container_title Cell metabolism
container_volume 28
creator Toledo, Miriam
Batista-Gonzalez, Ana
Merheb, Emilio
Aoun, Marie Louise
Tarabra, Elena
Feng, Daorong
Sarparanta, Jaakko
Merlo, Paola
Botrè, Francesco
Schwartz, Gary J.
Pessin, Jeffrey E.
Singh, Rajat
description 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. [Display omitted] •Core circadian proteins are temporally degraded by lysosomes•Loss of autophagy promotes CRY1 accumulation and disrupts the circadian clock•Autophagy drives gluconeogenesis by degrading CRY1•LIR motifs link CRY1 degradation to regulation of glucose homeostasis 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.
doi_str_mv 10.1016/j.cmet.2018.05.023
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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. [Display omitted] •Core circadian proteins are temporally degraded by lysosomes•Loss of autophagy promotes CRY1 accumulation and disrupts the circadian clock•Autophagy drives gluconeogenesis by degrading CRY1•LIR motifs link CRY1 degradation to regulation of glucose homeostasis 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. 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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. [Display omitted] •Core circadian proteins are temporally degraded by lysosomes•Loss of autophagy promotes CRY1 accumulation and disrupts the circadian clock•Autophagy drives gluconeogenesis by degrading CRY1•LIR motifs link CRY1 degradation to regulation of glucose homeostasis 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. 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subjects Animals
ARNTL Transcription Factors - metabolism
Autophagy
circadian clock
Circadian Clocks
Circadian Rhythm
CLOCK Proteins - metabolism
CRY1
Cryptochromes - metabolism
Diet, High-Fat - methods
FoxO1
Gluconeogenesis
Glucose - metabolism
Hyperglycemia - metabolism
LC3
liver
Liver - metabolism
lysosome
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins - metabolism
Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism
obesity
Proteolysis
title Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1
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