Nutrient‐sensitive transcription factors TFEB and TFE3 couple autophagy and metabolism to the peripheral clock

• Published in: The EMBO journal 2019-06, Vol.38 (12), p.n/a
• Main Authors: Pastore, Nunzia, Vainshtein, Anna, Herz, Niculin J, Huynh, Tuong, Brunetti, Lorenzo, Klisch, Tiemo J, Mutarelli, Margherita, Annunziata, Patrizia, Kinouchi, Kenichiro, Brunetti‐Pierri, Nicola, Sassone‐Corsi, Paolo, Ballabio, Andrea
• Format: Article
• Language: English
• Subjects: Ablation; Activation; Animals; Autophagy; Autophagy - drug effects; Autophagy - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - drug effects; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - physiology; Binding Sites; Cells, Cultured; Circadian Clocks - drug effects; Circadian Clocks - genetics; Circadian rhythm; Circadian Rhythm - drug effects; Circadian Rhythm - physiology; Circadian rhythms; Comparative analysis; Crosstalk; Deregulation; Diurnal; Diurnal variations; EMBO07; EMBO21; EMBO44; Energy metabolism; Energy Metabolism - drug effects; Energy Metabolism - genetics; Gene expression; Gene Expression Regulation; gene oscillation; Gene silencing; Genes; HEK293 Cells; Homeostasis; Humans; Machinery and equipment; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; MiT‐TFE; Muscles; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group D, Member 1 - physiology; Nutrients; Nutrients - pharmacology; Nutrients - physiology; Phagocytosis; Regulators; REV‐ERBα; Transcription factors; Transcription Factors - drug effects; Transcription Factors - genetics; Transcription Factors - physiology
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2018101347

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. Synopsis Autophagy and energy metabolism are regulated by nutrients and follow the circadian rhythm, but it is unclear whether common control mechanisms coordinate autophagy and the circadian clock. The crosstalk between TFEB/TFE3 transcription factors and REV‐ERBα repressor contributes to the circadian oscillation of autophagy. TFEB and TFE3 show a rhythmic activation over the 24‐h cycle. TFEB/TFE3 knockout mice display altered circadian behaviour. Transcriptional oscillation of autophagy genes is impaired in the liver and muscle of TFEB/TFE3 knockout mice. TFEB and TFE3 regulate the expression of clock machinery component REV‐ERBα in a clock‐independent manner. Transcriptional repression and induction by REV‐ERBα and TFEB/TFE3, respectively, contribute to the rhythmic expression of autophagy genes and to the circadian oscillation of autophagy. Graphical Abstract Crosstalk between TFEB/TFE3 transcription factors and REV‐ERBα repressor contributes to the circadian oscillation of autophagy.