A.I.2: The transcriptional control of autophagy in health and disease

Abstract

Autophagy mediates the organismal response to nutrient deprivation and plays an essential role in maintaining cellular homeostasis. Therefore, it is crucial to understand how this process is regulated by environmental cues. While the role of protein-protein interactions and of protein modifications in the regulation of autophagy has been studied in details, little attention has been given to the transcriptional regulation of this process. A systems biology approach led to the identification of TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. TFEB activity is regulated by its phosphorylation, which is mediated by the mTOR kinase on the lysosomal surface. Thus, a transcription factor and a kinase mediate a lysosome-to-nucleus signaling pathway that responds to environmental cues, such as nutrients, and in turn regulates autophagy and lysosomal biogenesis. In vivo studies in both liver and muscle have shown that modulation of TFEB activity has a profound impact on cellular clearance and energy metabolism and is a promising therapeutic target for a large variety of disease conditions.