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

Transcriptional regulation of autophagy and its implications in human disease

Yuchen Lei  1 , Daniel J Klionsky  2
Affiliations
Review

Transcriptional regulation of autophagy and its implications in human disease

Yuchen Lei et al. Cell Death Differ. 2023 Jun.

Abstract

Macroautophagy/autophagy is a conserved catabolic pathway that is vital for maintaining cell homeostasis and promoting cell survival under stressful conditions. Dysregulation of autophagy is associated with a variety of human diseases, such as cancer, neurodegenerative diseases, and metabolic disorders. Therefore, this pathway must be precisely regulated at multiple levels, involving epigenetic, transcriptional, post-transcriptional, translational, and post-translational mechanisms, to prevent inappropriate autophagy activity. In this review, we focus on autophagy regulation at the transcriptional level, summarizing the transcription factors that control autophagy gene expression in both yeast and mammalian cells. Because the expression and/or subcellular localization of some autophagy transcription factors are altered in certain diseases, we also discuss how changes in transcriptional regulation of autophagy are associated with human pathophysiologies.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Autophagy in mammalian cells and the essential protein complexes.
Following the induction of the ULK1 complex, which phosphorylates and activates PtdIns3K complex I, nucleation of the phagophore occurs. The expansion is facilitated by the two ubiquitin-like systems, which mediate the formation of the ATG12–ATG5-ATG16L1 complex and the conjugation of Atg8-family proteins with PE. When the expanding membrane closes and a complete autophagosome is generated, the outer membrane will fuse with the lysosome and forms an autolysosome; potential fusion with an endosome to generate an intermediate amphisome is not depicted for simplicity. The cargo within the autophagosome will subsequently be degraded and recycled.
Fig. 2
Fig. 2. Autophagy regulation at different levels.
In the nucleus, autophagy can be regulated at the epigenetic level, including DNA methylation and histone modifications (such as methylation and acetylation) and at the transcription level, which is basically controlled by the binding and release of transcription factors. After transcription, post-transcriptional regulation is performed by RNA binding proteins, non-coding RNAs and mRNA modification. Translation of autophagic mRNA can be regulated by some RNA binding proteins and controlled by the proteins in the core translation system, such as the requirement of EIF5A in ATG3 translation. After ATG protein synthesis, specific components can undergo post-translational modification, which affects protein activity and stability.
Fig. 3
Fig. 3. Transcriptional regulation of autophagy in yeast.
Under nutrient-rich conditions, TORC1 is activated. Multiple transcription repressors can bind to the promoter region of some core ATG genes, thus inhibiting autophagy. During starvation, TORC1 is inactivated. Rim15 will translocate into the nucleus and inhibit the transcription repression due to Ume6 and Rph1. Gln3, Gat1 and Gcn4 will also translocate into the nucleus and induce the transcription of ATG genes. The Spt4-Spt5 complex plays dual roles in regulating ATG gene transcription, inhibiting transcription when nutrients are replete and promoting transcription during starvation, which depends on the phosphorylation status of Spt5.
Fig. 4
Fig. 4. The regulation of autophagy in mammalian cells through TFEB, ZKSCAN3 and FOXO proteins.
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.
Fig. 5
Fig. 5. Transcription regulation of autophagy in mammalian cells.
The transcription factors that regulate autophagy (in addition to TFEB, ZKSCAN3 and FOXO proteins) are summarized. The transcription-independent functions of some proteins are also included.
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