P300/HDAC1 regulates the acetylation/deacetylation and autophagic activities of LC3/Atg8–PE ubiquitin-like system

Abstract

Protein acetylation plays potential roles in regulating autophagy occurrence. However, it varies greatly between yeast and mammals, and has not been thoroughly investigated in other organisms. Here, we reported that the components of BmAtg8–PE ubiquitin-like system (BmAtg3, BmAtg4, BmAtg7, and BmAtg8) in Bombyx mori were localized in the nucleus under nutrient-rich conditions, whereas they were exported to the cytoplasm upon autophagy induction. RNAi of BmP300 and inhibition of BmP300 activity resulted in nucleo-cytoplasmic translocation of BmAtg3 and BmAtg8, as well as premature induction of autophagy in the absence of stimulus. Conversely, RNAi of BmHDAC1 and inhibition of class I/II HADCs activities led to the nuclear accumulation of BmAtg3 and BmAtg8. In addition, acetylation sites in Atg proteins of BmAtg8–PE ubiquitin-like system were identified by mass spectrometry, and acetylation-site mutations caused nucleo-cytoplasmic translocation of BmAtg3, BmAtg4, and BmAtg8 along with autophagy promotion. Similarly, the subcellular localization of human ATG4b is determined by acetylation modification. In general, BmP300-mediated acetylation sequesters the components of BmAtg8–PE ubiquitin-like system in the nucleus, thus leading to the autophagy inhibition. Oppositely, BmHDAC1-mediated deacetylation leads to the nucleo-cytoplasmic translocation of the components of BmAtg8–PE ubiquitin-like system and promotes autophagy. This process is evolutionarily conserved between insects and mammals.

Transcription and Post-translational Regulation of Autophagy in Insects

“…In addition, the acetylation levels of Atg proteins from LC3/ BmAtg8-PE ubiquitin-like protein system are increased by histone acetyltransferase P300 while decreased by deacetylase HDAC1 in B. mori and human. Subsequently, deacetylation of the Atg proteins mediated by HDAC1 leads to their nucleocytoplasmic translocation and autophagy occurrence (Popelka and Klionsky, 2015;Wu et al, 2021a). These results show that the regulatory mechanism of acetylation in regulating autophagy is highly conserved in B. mori and mammals (Wu et al, 2021b).…”

“…Loss-of-function mutations of the acetylation sites lead to deacetylation and nucleo-cytoplasmic translocation of the four Atg proteins, and thereby promotion of autophagy. Collectively, acetylation/deacetylation of the molecular components from BmAtg8-PE ubiquitin-like protein system catalyzed by P300/HDAC1 mediates the occurrence of autophagy and is highly conserved from insects to mammals (Wu et al, 2021a).…”

“…20E induces while JH inhibits autophagy by antagonizing 20E signals (Liu et al, 2015;Tettamanti and Casartelli, 2019). Of note, the transcriptional and posttranslational regulators of autophagy are usually linked, e.g., 20E signaling induces the expression of Atg genes and inhibits acetylation of Atg proteins simultaneously; moreover, 20E also interacts with nutrient signaling to initialize autophagosome formation (Tian et al, 2013;Wu et al, 2021a). Here, we summarize the most recent progresses of autophagy mainly in D. melanogaster and B. mori to provide a deep thinking for further autophagy-related studies in insects.…”

Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells

“…Based on the findings of these studies altogether, VPA is likely to inhibit the mTOR pathway, dephosphorylating the HDAC1 [41]. This would prevent the translocation of HDAC1 into the nucleus, increasing acetylation of Atg4b, which is unlikely to catalyze the LC3/Atg8-PE required for autophagosome maturation [42]. The decreased autophagosome would eventually increase the stability of CCN1 protein, increasing the overall activity of CCN1 to promote osteogenesis.…”

“…Wu and his colleagues (2021) demonstrated that the mTOR pathway is activated by cholesterol derivatives that phosphorylate HDAC1 [41]. HDAC1 deacetylates autophagy-related protein 4b (Atg4b), which catalyzes the ubiquitin-like system, LC3/Atg8-phosphatidylethanolamine (PE), to generate autophagosome for degrading various cellular components [42]. Based on the findings of these studies altogether, VPA is likely to inhibit the mTOR pathway, dephosphorylating the HDAC1 [41].…”