Fig. 2.

Transcriptional control of autophagy. Transcriptional control of autophagy is mediated by multiple transcription factors, including ATF4, FoxOs and MiTF/TFE factors. Other factors that also induce autophagy genes are PPARα, p53, HIF1, NFkB and others but ATF4, FoxOs and MiTF/TFE factors do so in a more general manner. ATF4 is induced by amino acid deprivation, ER stress and mitochondrial dysfunction. In addition to inducing autophagy, ATF4 also induces genes involved in amino acid metabolism, systemic metabolism, protein refolding, antioxidant responses, and cell death genes that are activated if stress is not resolved. FoxOs are transcription factors that promote stemness and reduce aging and are activated by nutrient deprivation and redox stress. In addition to inducing general autophagy via ATG genes, FoxOs potently induce mitophagy via BNIP3 in atrophying muscle, cell cycle arrest in high redox states, and like ATF4 promotes cell death via Bim and Puma if cell stress is not removed. TFEB is the key factor of the MiTF/TFE transcription factor family that induces numerous autophagy genes (ATG) and lysosomal genes, and is subject to nutrient control via mTOR.