Acetylation modification in the regulation of macroautophagy

Abstract

Macroautophagy, commonly referred to as autophagy, is an evolutionarily conserved cellular process that plays a crucial role in maintaining cellular homeostasis. It orchestrates the delivery of dysfunctional or surplus cellular materials to the vacuole or lysosome for degradation and recycling, particularly during adverse conditions. Over the past few decades, research has unveiled intricate regulatory mechanisms governing autophagy through various post-translational modifications (PTMs). Among these PTMs, acetylation modification has emerged as a focal point in yeast and animal studies. It plays a pivotal role in autophagy by directly targeting core components within the central machinery of autophagy, including autophagy initiation, nucleation, phagophore expansion, and autophagosome maturation. Additionally, acetylation modulates autophagy at the transcriptional level by modifying histones and transcription factors. Despite its well-established significance in yeast and mammals, the role of acetylation in plant autophagy remains largely unexplored, and the precise regulatory mechanisms remain enigmatic. In this comprehensive review, we summarize the current understanding of the function and underlying mechanisms of acetylation in regulating autophagy across yeast, mammals, and plants. We particularly highlight recent advances in deciphering the impact of acetylation on plant autophagy. These insights not only provide valuable guidance but also inspire further scientific inquiries into the intricate role of acetylation in plant autophagy.

Keywords: Acetylation; Autophagy; Deacetylation; Lysine; Post-translational modification.

Fig. 1

Regulation of autophagy by acetylation of the core autophagic machinery. a Esa1-mediated acetylation of Atg3 promotes ATG8 lipidation during nutrient scarcity. Conversely, Rpd3 catalyzes the deacetylation of Atg3. b In Arabidopsis, HLS1-mediated acetylation of ATG18a (an ortholog of yeast Atg18) positively regulates autophagy. c Acetylation of ULK1 by TIP60 promotes the activity of ULK1, thereby initiating autophagy. d In mammals, p300mediated acetylation of both BECN1 and VPS34 inhibit autophagy. Conversely, SIRT1 or SIRT6 mediated deacetylation of BECN1 achieves the opposite effect. e Acetylation of ATG9A prevents autophagy under ER stress conditions. Conversely, SIRT1-mediated ATG9A deacetylation leads to autophagy induction. f p300-mediated acetylation of ATG4B, ATG5, ATG7, and ATG12 inhibits autophagy. In contrast, SIRT1-mediated deacetylation of ATG5, ATG7 and LC3, as well as SIRT2-mediated deacetylation of ATG4B, enhance autophagy. g Acetylation of cytoskeleton proteins affects the activity of autophagy. h CBP and HDAC2 act as a molecular switch to modulate the acetylation of STX17. CBP-mediated acetylation of STX17 inhibits its activity, while HDAC2-mediated deacetylation of STX17 promotes the formation of the STX17-SNAP29-VAMP8 complex under starvation conditions. This complex is essential for autophagosome-lysosome fusion. Additionally, TIP60-mediated acetylation of RUBCNL facilitates HOPS complex recruitment, thereby promoting autophagosome maturation. Ac, acetylation; ATAT1, -tubulin acetyltransferase 1; ATG, autophagy-related; ATP13A2, ATPase cation transporting 13A2; BECN1, beclin 1; CSB, cockayne syndrome group B; bpV(phen), potassium bisperoxo (1,10-phenanthroline)oxovanadate; Esa1, essential SAS2-related acetyltransferase 1; FIP200, family-interacting protein of 200 kDa; HDAC6, histone deacetylase 6; LC3, microtubule-associated protein 1 light chain 3; MEC-17/TAT-1, -tubulin acetyltransferase-1; p300, E1A binding protein 300; p62/SQSTM1, sequestosome 1; PE, phosphatidylethanolamine; PtdIns(3)P, phosphatidylinositol 3-phosphate; ROS, reactive oxygen species; Rpd3, reduced potassium dependency-3; RUBCNL/Pacer, rubicon like autophagy enhancer; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT6, sirtuin 6; TIP60, HIV-1 Tat interactive protein 60 kD; ULK1, unc-51-like kinase1; VPS15/PIK3R4, phosphoinositide 3-kinase regulatory subunit 4; VPS34/PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3

Fig. 2

Epigenetic regulation of autophagy by histone acetylation. a In ageing yeast, spermidine inhibits the activity of HATs, such as Iki3p and Sas3p. This inhibition leads to decreased acetylation of H3 and upregulation of autophagyrelated genes. b Upon glucose deprivation, AMPK phosphorylates ACSS2, promoting its nuclear translocation. In the nucleus, ACSS2 binds to TEEB and locally produces acetyl-CoA for H3 acetylation in the promoter regions of autophagy-related and lysosomal genes, thereby activating gene expression. c The MYC protein cooperates with HDACs, specifically HDAC2, to suppress the transcription of autophagic and lysosomal. This suppression occurs through modulation of H3K14 acetylation and the occupancy of transcription factors TFEB, TFE3, and FOXH1 in the promoter regions of these genes. d Acetylation of H3K9 and H3K27 activates the expression of autophagy-related genes. e Treatment with short-chain fatty acids induces HDAC2 inhibition, leading to increased H3K27ac in the ULK1 promoter. Consequently, ULK1 transcription is upregulated. f Reduction of H4K16 acetylation, either through downregulation of KAT8/hMOF/MYST1 or deacetylation of H4K16 mediated by SIRT1, results in transcriptional repression of autophagy-related genes. g Overexpression of histone HIST1H1C/H1.2 upregulates SIRT1 and HDAC1, leading to reduced acetylation of H4K16. This reduction promotes the transcription of autophagy-related genes. h In Arabidopsis, HAD9-mediated histone deacetylation of H3K9 and H3K27 suppresses the expression of autophagic genes. ACSS2, acetyl-CoA synthetase 2; ATG, autophagy-related; Elp1/Iki3p, Elongator Acetyltransferase Complex Subunit 1; FOXH1, Forkhead Box H1; H3, histone 3; H4, histone 4; HATs, acetyltransferases; HDACs, deacetylases; HDA9, HISTONE DEACETYLASE9; K, lysine; KAT8, lysine acetyltransferase 8; MYC, BHLH transcription factor; Sas3p, the catalytic subunit of NuA3 HAT complex; SIRT1, sirtuin 1; TFEB, transcription factor EB; TFE3, Transcription Factor Binding to IGHM Enhancer 3; ULK1, unc-51-like kinase1

Fig. 3

Regulation of autophagy by acetylation of transcription factors. a CBP-mediated acetylation of FOXO1 at K242, K245, and K262 attenuates its transcriptional activity, leading to down-regulation of autophagy-related genes. Correspondingly, the acetylation of FOXO1 can be reversed by SIRT1 in cardiac myocytes. b SIRT1 deacetylates FOXO3 to transcriptionally inhibiting autophagy in skeletal muscle. c Under Angiotensin II treatment, HDAC4-mediated FOXO3a deacetylation promotes autophagy at transcriptional level, which in turn promotes vascular inflammation. d In SAHA-treated cells, enhanced TFEB acetylation at K91, K103, K116, and K430 catalyzed by ACAT1 increases its transcriptional activity. Consequently, autophagy and lysosomal genes are upregulated. Notably, this acetylation can be reversed by HDAC2. e Acetylation of TFEB at K274 and K279 by GCN5 disrupts its DNA binding, resulting in the inhibition of transcription for autophagy and lysosomal genes. Conversely, SIRT1-mediated deacetylation of TFEB at K116 transcriptionally activating the expression of its downstream targets. ACAT1, acetyl-coenzyme A acetyltransferase 1; CBP, CREB binding protein; FOXO1, Forkhead Box O1; FOXO3, Forkhead Box O3; GCN5, general control non-repressed protein 5; HDAC2, histone deacetylase 2; HDAC4, histone deacetylase 4; K, lysine; SIRT1, sirtuin 1; TEEB, transcription factor EB