Abstract
Lysine acetylation is a widespread and versatile protein post-translational modification. Lysine acetyltransferases and lysine deacetylases catalyse the addition or removal, respectively, of acetyl groups at both histone and non-histone targets. In this Review, we discuss several features of acetylation and deacetylation, including their diversity of targets, rapid turnover, exquisite sensitivity to the concentrations of the cofactors acetyl-CoA, acyl-CoA and NAD+, and tight interplay with metabolism. Histone acetylation and non-histone protein acetylation influence a myriad of cellular and physiological processes, including transcription, phase separation, autophagy, mitosis, differentiation and neural function. The activity of lysine acetyltransferases and lysine deacetylases can, in turn, be regulated by metabolic states, diet and specific small molecules. Histone acetylation has also recently been shown to mediate cellular memory. These features enable acetylation to integrate the cellular state with transcriptional output and cell-fate decisions.
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Acknowledgements
The authors thank all past and current members of the Akhtar laboratory for stimulating scientific discussions, and in particular T. H. Tsang, A. Panhale, B. Sheikh, M. Samata, U. Erdogdu, T. Rumpf, C. Pessoa Rodrigues, A. Alexiadis, M. Wiese and T. Kulkarni for constructive comments on the manuscript. Research in the Akhtar laboratory is supported by the Max Planck Society (MPG); and by the German Research Foundation (DFG) under Germany’s Excellence Strategy (Centre for Integrative Biological Signalling Studies, EXC-2189, project ID 390939984), CRC 992 (A02), CRC 1425 (P04) and CRC 1381 (B3) awarded to A.A.
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Glossary
- Stoichiometry
-
The proportion of the total protein pool that is modified by acetylation at a particular Lys residue at a particular time.
- Acetylome
-
A high-throughput profile of all acetylated proteins and residues in a particular peptide mixture detected by mass spectrometry.
- H2A–H2B acidic patch
-
A 3D surface formed by acidic amino acids in histone H2A (Glu56, Glu61, Glu64, Asp90, Glu91 and Glu92) and histone H2B (Glu110) in an assembled nucleosome.
- Bromodomain and extra-terminal domain
-
(BET). Refers to a family of four proteins — BRDT, BRD2, BRD3 and BRD4 — in humans and mice. Each BET protein carries two bromodomains.
- Nucleosome-remodelling factors
-
A large family of proteins with ATPase activity that repositions nucleosomes along the DNA through nucleosome sliding, spacing and eviction or by collaborating with histone chaperones to assemble nucleosomes on DNA.
- Stress granules
-
Transient membraneless cytoplasmic ribonucleoprotein organelles whose assembly is induced by specific cellular stresses.
- RNA recognition motif
-
(RRM). A canonical RNA-binding protein domain consisting of two α-helices packed on an antiparallel four-stranded β-sheet.
- Inclusion bodies
-
Membraneless cytoplasmic proteinaceous or ribonucleoprotein assemblies associated with neurodegenerative disorders.
- Intrinsically disordered regions
-
(IDRs). Segments of protein that do not autonomously adopt a specific 3D structure and that are thought to display conformational heterogeneity.
- Acyl-CoA synthetase short-chain family member
-
The enzymes ACSS1, ACSS2 and ACSS3 synthesize acetyl-CoA from acetate. ACSS1 and ACSS3 are found in the mitochondrial matrix, whereas ACSS2 is located in the cytoplasm and nucleus.
- ATP-citrate synthase
-
(ACLY). A synthase found in the nucleus and cytoplasm that converts citrate into acetyl-CoA and oxaloacetate.
- Pyruvate dehydrogenase complex
-
A complex that produces acetyl-CoA from the pyruvate precursor. It is normally found in mitochondria, but can translocate to the nucleus according to the cell cycle stage and in response to certain stimuli.
- Pathological tau transformation
-
The process by which hyperphosphorylated tau facilitates aggregation and disengagement of soluble tau protein from microtubules to form tau tangles.
- Tau tangles
-
Aggregates or inclusions of hyperphosphorylated tau, also known as neurofibrillary tangles. The presence of tau tangles is a characteristic feature of Alzheimer disease.
- Chromothripsis
-
A large-scale mutational process that generates extensive chromosomal rearrangements.
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Shvedunova, M., Akhtar, A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol 23, 329–349 (2022). https://doi.org/10.1038/s41580-021-00441-y
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DOI: https://doi.org/10.1038/s41580-021-00441-y
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