Figure 3.

Transcriptional regulation of autophagy and lysosome biogenesis. Under nutrient replete conditions, TFEB is phosphorylated by mTORC1 on conserved serine residues, which inhibits its nuclear translocation and activation. Negative transcriptional regulators of autophagosome and lysosome biogenesis are also activated including ZKSCAN3, and Farnesoid X Receptor (FXR). ZKSCAN3 binds to the promoters of lysosomal and autophagic genes and blocks their expression. FXR binds and displaces positive transcriptional regulators such as cAMP response element-binding protein (CREB) by disrupting formation of a complex between CREB and its co-activator CRTC2. FXR also displaces peroxisome proliferator activator receptor-a (PPARα) from binding to promoter regions upstream of autophagy and lysosome genes. Hence the cumulative effect is suppression of autophagy and lysosome gene induction under nutrient replete conditions. In contrast, starvation results in de-phosphorylation of TFEB via the combined action of calcineurin and inactivation of mTORC1. This allows for nuclear translocation of TFEB and binding to CLEAR elements present within the promoters of target genes. Starvation also inactivates FXR, enabling formation of the CREB-CRTC2 complex, which in turn activates TFEB transcription. Similarly suppression of FXR allows PPARα to activate autophagy and lysosme gene expression.