Nutrient‐sensitive transcription factors TFEB and TFE 3 couple autophagy and metabolism to the peripheral clock

Abstract

Autophagy and energy metabolism are known to follow a circadian pattern. However, it is unclear whether autophagy and the circadian clock are coordinated by common control mechanisms. Here, we show that the oscillation of autophagy genes is dependent on the nutrient‐sensitive activation of TFEB and TFE3, key regulators of autophagy, lysosomal biogenesis, and cell homeostasis. TFEB and TFE3 display a circadian activation over the 24‐h cycle and are responsible for the rhythmic induction of genes involved in autophagy during the light phase. Genetic ablation of TFEB and TFE3 in mice results in deregulated autophagy over the diurnal cycle and altered gene expression causing abnormal circadian wheel‐running behavior. In addition, TFEB and TFE3 directly regulate the expression of Rev‐erbα (Nr1d1), a transcriptional repressor component of the core clock machinery also involved in the regulation of whole‐body metabolism and autophagy. Comparative analysis of the cistromes of TFEB/TFE3 and REV‐ERBα showed an extensive overlap of their binding sites, particularly in genes involved in autophagy and metabolic functions. These data reveal a direct link between nutrient and clock‐dependent regulation of gene expression shedding a new light on the crosstalk between autophagy, metabolism, and circadian cycles.

Autophagy: clocking in for the night shift

“…Disruptions of these biological rhythms, such as shiftwork, can be detrimental resulting in a predisposition to certain metabolic diseases (Karlsson et al , ). Pastore et al () discovered a mechanism linking the circadian molecular clock, a transcription–translation feedback loop, and the nutrient‐responsive clock. The solar day–night cycle is coupled with the circadian molecular clock, which regulates diurnal gene expression, through blue light sensed by the retina and transmitted to the hypothalamic suprachiasmatic nucleus (SCN).…”

De novomutations in the X-linkedTFE3gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

“…Muscle biopsy, performed in two individuals from this cohort, showed fat and glycogen accumulation, muscular fibre size irregularity, without evidence of mitochondrial dysfunction. Interestingly in the more recent data, evidences showing that TFE3 plays a role in the regulation of the circadian oscillations of the expression of genes involved in autophagy and lipid metabolism, and that Tfe3 knock-out mice had abnormal circadian behaviour 40. Indeed, in our series, five patients (29%) were noted to have sleep disturbance: this could be due to circadian rhythms alteration.…”

Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics

“…The adopted orphan NR—REV-ERBα—is involved in adipogenesis, muscle differentiation, glucose/lipid metabolism, and the circadian rhythm [ 161 , 162 , 163 ]. REV-ERBα links the circadian rhythm and autophagy, and directly regulates the rhythmic expression of ATGs in zebrafish [ 164 ].…”