Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1

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.

Expression of mutant CHMP2B linked to neurodegeneration in humans disrupts circadian rhythms inDrosophila

“…31,40,41 The autophagy pathway was shown to play a modulatory role in degradation of CRY1 and BMAL1 (mammalian homolog of Cycle) during circadian regulation of glucose metabolism in mice liver. 42,43 The autophagy pathway and TOR pathway (a negative regulator of autophagy) were shown to regulate circadian locomotor rhythms. 44 Ectopic expression of mutant Shibire (Drosophila homolog of Dynamin)-an ATPase required for scission of plasma membrane to form endocytic vesicles, causes disruption of circadian rhythm.…”

One Actor, Multiple Roles: The Performances of Cryptochrome in Drosophila

“…(LC3)-interacting region (LIR) motifs are found in the CRY1 sequence, and their role has been confirmed by the observation that mice in which autophagy is genetically blocked exhibit accumulation of CRY1 and disruption of the circadian clock in the liver (Toledo et al, 2018). Moreover, autophagic degradation of CRY1 is important in maintaining blood glucose levels by driving gluconeogenesis (Toledo et al, 2018). As in mammals (Turek et al, 2005;Green et al, 2008), the circadian clock is involved in fat storage and mobilization also in Drosophila.…”

“…Moreover, CRY1 interacts with the autophagosome marker light chain 3 (LC3), responsible for its time-dependent autophagic degradation (Toledo et al, 2018). (LC3)-interacting region (LIR) motifs are found in the CRY1 sequence, and their role has been confirmed by the observation that mice in which autophagy is genetically blocked exhibit accumulation of CRY1 and disruption of the circadian clock in the liver (Toledo et al, 2018). Moreover, autophagic degradation of CRY1 is important in maintaining blood glucose levels by driving gluconeogenesis (Toledo et al, 2018).…”

The importance of being rhythmic: Living in harmony with your body clocks

“…124 CRY1 and CRY2 proteins reduce fasting glucose production by inhibiting glucagon-induced DIBNER liver gluconeogenesis. 110,125,126 Moreover, CRY1 levels are decreased by autophagy in rodent liver, providing a link between autophagy, increased gluconeogenesis and the overall maintenance of glucose homeostasis. 126 Furthermore, diet-induced obesity in wild-type mice causes remodelling of the circadian liver enhancer landscape, leading to massive changes in lipid metabolism via SREBP and PPARα.…”

“…110,125,126 Moreover, CRY1 levels are decreased by autophagy in rodent liver, providing a link between autophagy, increased gluconeogenesis and the overall maintenance of glucose homeostasis. 126 Furthermore, diet-induced obesity in wild-type mice causes remodelling of the circadian liver enhancer landscape, leading to massive changes in lipid metabolism via SREBP and PPARα. 127 Additionally, the RNA-binding protein NONO situated in liver cell nuclei couples the rhythmic expression of metabolic genes with nutrient levels, with NONO-deficient mice exhibiting impaired glucose tolerance as well as lower hepatic glycogen and lipid content.…”