BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy

Significance Autophagy allows the lysosomal degradation of intracellular material. It is a tightly regulated process controlled by the tumor-suppressor gene p53, among others. Here we report a unique regulator of autophagy, BAT3, which modulates the intracellular localization of the enzyme p300, an enzyme that adds some acetyl residues on targets proteins (acetylation) to modulate their activity. To stimulate autophagy, BAT3 allows the acetylation of p53 by p300 in the nucleus, but limits the p300-dependent acetylation of ATG7, a protein specific for autophagy, in the cytosol. Thus, BAT3 acts on both the cytosol and the nucleus to tightly modulate autophagy. Autophagy is regulated by posttranslational modifications, including acetylation. Here we show that HLA-B–associated transcript 3 (BAT3) is essential for basal and starvation-induced autophagy in embryonic day 18.5 BAT3−/− mouse embryos and in mouse embryonic fibroblasts (MEFs) through the modulation of p300-dependent acetylation of p53 and ATG7. Specifically, BAT3 increases p53 acetylation and proautophagic p53 target gene expression, while limiting p300-dependent acetylation of ATG7, a mechanism known to inhibit autophagy. In the absence of BAT3 or when BAT3 is located exclusively in the cytosol, autophagy is abrogated, ATG7 is hyperacetylated, p53 acetylation is abolished, and p300 accumulates in the cytosol, indicating that BAT3 regulates the nuclear localization of p300. In addition, the interaction between BAT3 and p300 is stronger in the cytosol than in the nucleus and, during starvation, the level of p300 decreases in the cytosol but increases in the nucleus only in the presence of BAT3. We conclude that BAT3 tightly controls autophagy by modulating p300 intracellular localization, affecting the accessibility of p300 to its substrates, p53 and ATG7.