Review
Acetylation of non-histone proteins modulates cellular signalling at multiple levels

https://doi.org/10.1016/j.biocel.2008.08.027Get rights and content

Abstract

This review focuses on the posttranslational acetylation of non-histone proteins, which determines vital regulatory processes. The recruitment of histone acetyltransferases and histone deacetylases to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation and differentiation. A steadily growing number of identified acetylated non-histone proteins demonstrate that reversible lysine acetylation affects mRNA stability, and the localisation, interaction, degradation and function of proteins. Interestingly, most non-histone proteins targeted by acetylation are relevant for tumourigenesis, cancer cell proliferation and immune functions. Therefore inhibitors of histone deacetylases are considered as candidate drugs for cancer therapy. Histone deacetylase inhibitors alter histone acetylation and chromatin structure, which modulates gene expression, as well as promoting the acetylation of non-histone proteins. Here, we summarise the complex effects of dynamic alterations in the cellular acetylome on physiologically relevant pathways.

Section snippets

Histone acetylation

Eukaryotic DNA, histones and histone-like proteins are assembled into nucleosomes. Histones, the main protein component of chromatin, not merely play a role in packaging DNA. The tails and the globular domains of histones can be modified by acetylation, phosphorylation, methylation, ubiquitination, sumoylation, and less commonly by citrullination and ADP-ribosylation. These posttranslational modifications can alter DNA-histone interactions or the binding of proteins, such as transcription

HDACs and SIRTs

HATs catalyse the transfer of an acetyl group from acetyl-CoA to the ɛ-NH2 group of the amino acid side chain of lysine residues. Acetylation of lysine residues at the ɛ-NH2 is highly dynamic. The first deacetylase activity was identified back in the 1960s (Inoue and Fujimoto, 1969), soon after the discovery of histone acetylation and its potential role in the regulation of gene expression (Allfrey et al., 1964, Phillips, 1963). Since histones were the first identified targets of deacetylases,

HATs

Since the discovery of the first HAT enzyme, the yeast Hat1 (Kleff et al., 1995), a lot of attention has been drawn to these enzymes. HATs are evolutionarily conserved from yeast to man and form multiple subunit complexes (Kimura et al., 2005). Unlike HDACs, HATs are more diverse in structure and function (Yang, 2004). In mammals, over 30 HATs display distinct substrate specificities for histones and non-histone proteins. HATs do not acetylate lysine moieties randomly. Crystal structure

Non-histone targets of HDACs and HATs—the acetylome

Lysine side chains can be acetylated, methylated (mono-, di- or trimethylation), ubiquitinated (mono- or polyubiquitination), sumoylated and ADP-ribosylated (Merrick and Duraisingh, 2007). These rivalling and reversible posttranslational modifications are regulated by a complex interplay of different enzymes. Reversible acetylation of lysine ɛ-amino groups crucially modulates protein function und cellular networks (Fig. 1). In eukaryotic cells, acetylation is among the most common covalent

Acetylation regulates multiple processes from gene expression to protein activity

Acetylation can affect signalling pathways and thereby alter cell fate and function. mRNA splicing, mRNA transport, mRNA integrity, translation, protein activity, protein localisation, protein stability and interactions are regulated by acetylation. Hence, acetylation can interfere with every step of regulatory processes from signalling to transcription to protein degradation.

Conclusion

Aberrant lysine acetylation has been reported in malignant cells (Yang, 2004), and HATs and HDACs are closely linked to severe diseases such as cancer, neurodegeneration, cardiovascular disorders, inflammatory lung diseases, as well as to ageing (Blander and Guarente, 2004, Carrozza et al., 2003, Heinzel and Krämer, 2007, Ito et al., 2007, McKinsey and Olson, 2004, Saha and Pahan, 2006). The previous view that HDACi modulate gene expression mainly by histone acetylation appears to be too

Acknowledgements

We apologise to authors whose research articles could not be cited due to space limitations. This work was supported by the Deutsche Forschungsgemeinschaft (DFG).

References (230)

  • T. Bouras et al.

    SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1

    J Biol Chem

    (2005)
  • M.J. Carrozza et al.

    The diverse functions of histone acetyltransferase complexes

    Trends Genet

    (2003)
  • W.G. Deng et al.

    Up-regulation of p300 binding and p50 acetylation in tumor necrosis factor-alpha-induced cyclooxygenase-2 promoter activation

    J Biol Chem

    (2003)
  • J.M. Denu

    The Sir 2 family of protein deacetylases

    Curr Opin Chem Biol

    (2005)
  • L.K. Durrin et al.

    Yeast histone H4 N-terminal sequence is required for promoter activation in vivo

    Cell

    (1991)
  • D.J. Ellis et al.

    Histone acetylation is not an accurate predictor of gene expression following treatment with histone deacetylase inhibitors

    Biochem Biophys Res Commun

    (2008)
  • J.M. Espinosa et al.

    Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment

    Mol Cell

    (2001)
  • R.A. Frye

    Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity

    Biochem Biophys Res Commun

    (1999)
  • M. Fulco et al.

    Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state

    Mol Cell

    (2003)
  • L. Gao et al.

    Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family

    J Biol Chem

    (2002)
  • P. George et al.

    Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3

    Blood

    (2005)
  • M.A. Glozak et al.

    Acetylation and deacetylation of non-histone proteins

    Gene

    (2005)
  • P.A. Grant et al.

    Histone acetyltransferase complexes

    Semin Cell Dev Biol

    (1999)
  • I.V. Gregoretti et al.

    Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis

    J Mol Biol

    (2004)
  • E. Grönroos et al.

    Control of Smad7 stability by competition between acetylation and ubiquitination

    Mol Cell

    (2002)
  • C.M. Grozinger et al.

    Deacetylase enzymes: biological functions and the use of small-molecule inhibitors

    Chem Biol

    (2002)
  • C.M. Grozinger et al.

    Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening

    J Biol Chem

    (2001)
  • E.A. Grzybowska et al.

    Regulatory functions of 3′UTRs

    Biochem Biophys Res Commun

    (2001)
  • W. Gu et al.

    Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain

    Cell

    (1997)
  • L. Guarente

    Mitochondria—a nexus for aging, calorie restriction, and sirtuins?

    Cell

    (2008)
  • M.S. Hayden et al.

    Shared principles in NF-kappaB signaling

    Cell

    (2008)
  • T. Heinzel et al.

    Pharmacodynamic markers for histone deacetylase inhibitor development

    Drug Discovery Today

    (2007)
  • C.L. Hirsch et al.

    Histone deacetylase inhibitors regulate p21WAF1 gene expression at the post-transcriptional level in HepG2 cells

    FEBS Lett

    (2004)
  • N. Huang et al.

    Inhibition of IL-8 gene expression in Caco-2 cells by compounds which induce histone hyperacetylation

    Cytokine

    (1997)
  • A. Ianari et al.

    Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in response to DNA damage

    J Biol Chem

    (2004)
  • M.S. Inan et al.

    The luminal short-chain fatty acid butyrate modulates NF-kappaB activity in a human colonic epithelial cell line

    Gastroenterology

    (2000)
  • A. Inoue et al.

    Enzymatic deacetylation of histone

    Biochem Biophys Res Commun

    (1969)
  • K. Ito et al.

    Impact of protein acetylation in inflammatory lung diseases

    Pharmacol Ther

    (2007)
  • R. Januchowski et al.

    Trichostatin A down-regulate DNA methyltransferase 1 in Jurkat T cells

    Cancer Lett

    (2007)
  • J.W. Jeong et al.

    Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation

    Cell

    (2002)
  • Y.H. Jin et al.

    Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation

    J Biol Chem

    (2004)
  • L.J. Juan et al.

    Histone deacetylases specifically down-regulate p53-dependent gene activation

    J Biol Chem

    (2000)
  • E. Adam et al.

    Potentiation of tumor necrosis factor-induced NF-kappa B activation by deacetylase inhibitors is associated with a delayed cytoplasmic reappearance of I kappa B alpha

    Mol Cell Biol

    (2003)
  • V.G. Allfrey et al.

    Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis

    Proc Natl Acad Sci USA

    (1964)
  • C.D. Allis et al.

    Deposition-related histone acetylation in micronuclei of conjugating tetrahymena

    Proc Natl Acad Sci USA

    (1985)
  • T. Araki et al.

    Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration

    Science

    (2004)
  • B.P. Ashburner et al.

    The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression

    Mol Cell Biol

    (2001)
  • A. Atmaca et al.

    Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial

    Br J Cancer

    (2007)
  • P. Bali et al.

    Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3

    Clin Cancer Res

    (2004)
  • J.A. Baur et al.

    Resveratrol improves health and survival of mice on a high-calorie diet

    Nature

    (2006)
  • Cited by (576)

    • Epigenetic biomarkers: Where are we in cancer therapy

      2023, Epigenetics in Human Disease, Third Edition
    View all citing articles on Scopus
    View full text