Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
EMBO J. 2019 Jun 17;38(12). doi: 10.15252/embj.2018101347. Epub 2019 May 24.
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 (), 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.
自噬和能量代谢已知遵循昼夜节律模式。然而，尚不清楚自噬和生物钟是否通过共同的控制机制来协调。在这里，我们表明，自噬基因的振荡依赖于营养敏感的 TFEB 和 TFE3 的激活，TFEB 和 TFE3 是自噬、溶酶体生物发生和细胞内稳态的关键调节剂。TFEB 和 TFE3 在 24 小时周期内表现出昼夜激活，并负责在光相期间诱导与自噬相关的基因的节律性诱导。TFEB 和 TFE3 在小鼠中的基因缺失会导致昼夜周期中自噬的失调和基因表达的改变，从而导致异常的昼夜轮跑行为。此外，TFEB 和 TFE3 直接调节 () 的表达，() 是核心时钟机制的转录抑制因子组件，也参与全身代谢和自噬的调节。TFEB/TFE3 和 REV-ERBα 的 cistrome 的比较分析显示，它们的结合位点广泛重叠，特别是在参与自噬和代谢功能的基因中。这些数据揭示了营养和时钟依赖性基因表达调控之间的直接联系，为自噬、代谢和昼夜节律之间的串扰提供了新的见解。
