Keeping the autophagy tempo

Abstract

Most essential physiological functions in mammals show a 24-h rhythmic pattern, which includes sleep-wake, feeding-non-feeding cycles and energy metabolism. Recent studies indicate that macroautophagy/autophagy also displays a robust circadian rhythmicity following the daily feeding pattern in adult mammals. We discovered that MiT-TFE transcription factors TFEB and TFE3, master regulators of autophagy and lysosomal biogenesis, are activated in a circadian manner and drive the expression of NR1D1/REV-ERBα, a key component of the core clockwork, thus revealing a molecular link between the nutrient-driven circadian cycle and the light-induced molecular clock. The dynamic balance between TFEB and TFE3 activation and NR1D1 expression is responsible for the modulation and oscillation of autophagy and metabolism genes.

Keywords: Autophagy; NR1D1/REV-ERBα; TFEB/TFE3; circadian rhythm; gene oscillation.

Figure 1.

The nutrient-sensitive factors TFEB and TFE3 link autophagy to the circadian molecular clock. In normal conditions, TFEB and TFE3 translocate to the nucleus in the absence of nutrients (light phase) and induce the expression of genes involved in autophagy and metabolism. NR1D1, activated by both circadian signals and TFEB or TFE3 at Zeitgeber time (ZT) 8, inhibits the expression of its targets including autophagy genes. Nutrients activate MTOR in the dark phase, contributing to the inactivation of TFEB and TFE3 and the complete inhibition of autophagy. In the absence of TFEB and TFE3, autophagy is blunted during the light phase and loses the oscillatory pattern due to the reduced expression of NR1D1. Thus, the crosstalk between TFEB and TFE3, NR1D1 and MTOR contributes to circadian oscillation of autophagy.