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

Abstract

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.degradation | signalisation | nucleo-cytoplasmic shuttling A utophagy allows the lysosomal degradation of intracellular macromolecules and organelles after their sequestration in a vacuole known as the autophagosome (1). Basal autophagy is a cytoplasmic quality control mechanism that limits the production of reactive oxygen species and genomic instability. Autophagy is also induced to improve cell survival under stress.Signaling pathways involved in the regulation of autophagy have been widely studied (2). Autophagy is modulated at two levels: (i) the molecular machinery involved in autophagosome biogenesis, dependent on specific genes known as Atg (AuTophaGy) genes, and (ii) the upstream signaling pathways (e.g., PI3K, MAPK, mTOR) that act on ATG proteins. Posttranslational modifications are crucial for the regulation of autophagy. The first example came from Y. Oshumi's laboratory with the discovery of the conjugation systems for the ATG5-ATG12 and ATG8-phosphatidylethanolamine complexes in yeast (3). Phosphorylation is probably the most thoroughly investigated posttranslational event in autophagy. It appears that modulation of acetylation also affects Atg gene expression or activity; for instance, acetylation of the Unc-51-like kinase 1 (ULK1) (mammalian homolog of ATG1) by the acetylase Tat interacting protein 60 kDa (TIP60) induces autophagy after growth factor deprivation (4). In yeast, ESA1-dependent acetylation of ATG3 is essential for its interaction with ATG8 and ATG8 lipidation (5). Conversely, acetylation of ATG5, ATG7, microtubule associated protein 1 light chain 3 (LC3), and ATG12 by the acetyltransferase p300 inhibits autophagy (6), whereas their deacetylation by Sirtuins 1 (SIRT1) stimulates autophagy (7).HLA-B-associated transcript 3 (BAT3) is a nucleo-cytoplasmic shuttling protein that contains, among other, a nuclear export signal (NES) and...

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

“…In the absence of BAG6 or when this protein is located exclusively in the cytosol, macroautophagy is abrogated, ATG7 is hyperacetylated, TP53 acetylation is abolished, and EP300 accumulates in the cytosol, indicating that BAG6 regulates the nuclear localization of EP300. 1635 BARA (b-a repeated, autophagy-specific): A domain at the C terminus of Vps30/Atg6 that is required for targeting PtdIns3K complex I to the PAS. 1636 The BARA domain is also found at the C terminus of BECN1 and in UVRAG.…”

Benzene induces haematotoxicity by promoting deacetylation and autophagy

“…Accumulating evidence shows that acetylation of autophagic components is rather complex and mainly regulated by a major acetyltransferase p300 and a NAD + ‐dependent deacetylase Sirt1 . p300 has been reported to be required for autophagy and capable of acetylating ATG7, LC3, and ATG3 . The acetylation of histone H3 can reflect the activity of p300 as p300 directly acetylates histone H3 on lysine 56 .…”

Epigenetic modifications as regulatory elements of autophagy in cancer

“…Knockdown of EP300 activated autophagy, whereas overexpression of EP300 inhibited starvation-induced autophagy [45]. BAG6/BAT3 (BCL2-associated athanogene 6) was demonstrated to control basal and starvation-induced autophagy via limiting EP300-dependent acetylation of Atg7 [46,47]. KAT5/ TIP60 as a member of MYST family can be activated by GSK3 (glycogen synthase kinase-3), which in turn directly acetylates and stimulates the protein kinase ULK1 that is required for the induction of autophagy [48].…”