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. 2023 Apr 12;30(6):1416–1429. doi: 10.1038/s41418-023-01162-9

Fig. 4. The regulation of autophagy in mammalian cells through TFEB, ZKSCAN3 and FOXO proteins.

Fig. 4

Under nutrient-replete conditions, TFEB is phosphorylated by both MTORC1 and MAPK1, and phosphorylated TFEB will be retained int the cytosol. At the same time, ZKSCAN3 suppresses the transcription of autophagy and lysosome genes. FOXO3 is phosphorylated by AKT and binds to YWHA/14-3-3 proteins, which will exit from the nucleus. Upon starvation, dephosphorylated TFEB is transported into the nucleus and transactivates a series of genes involved in autophagy and lysosome function. In contrast, ZKSCAN3 is pushed outside the nucleus. FOXO3 maintains its nuclear localization and induces the transcription of multiple ATG genes. FOXO3 also promotes the expression of PIK3CA which induces the subsequent phosphorylation of FOXO1. Phosphorylated FOXO1 will move into the cytosol and binds to ATG7 to induce autophagy through a transcription-independent pathway.