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

Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
The International Journal of Biochemistry & Cell Biology (Impact Factor: 4.05). 10/2008; 41(1):185-98. DOI: 10.1016/j.biocel.2008.08.027
Source: PubMed


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.

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Available from: Tobias Wagner, Jul 30, 2014
    • "Histone deacetylase (HDAC) activities are essential for the removal of acetyl groups from the -amino group of lysine residues leading to modulation of activity, cellular localization or stability of targeted proteins [1] [2] [3]. The HDAC family contains eighteen members divided in four classes: class I (HDAC1, 2, 3, 8), class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10), class III (sirtuins 1 to 7) and class IV (HDAC11). "
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    ABSTRACT: Histone deacetylase (HDAC)6 is a unique isoenzyme targeting specific substrates including α-tubulin and heat shock protein (HSP)90. HDAC6 is involved in protein trafficking and degradation, cell shape and migration. Deregulation of HDAC6 activity is associated with a variety of diseases including cancer leading to a growing interest for developing HDAC6 inhibitors. Here, we identified two new structurally related 4-hydroxybenzoic acids as selective HDAC6 inhibitors reducing proliferation, colony and spheroid formation as well as viability of prostate cancer cells. Both compounds strongly enhanced α-tubulin acetylation leading to remodeling of microtubular organization. Furthermore, 4-hydroxybenzoic acids decreased HSP90α regulation of the human androgen receptor in prostate cancer cells by increasing HSP90α acetylation levels. Collectively, our data support the potential of 4-hydroxybenzoic acid derivatives as HDAC6-specific inhibitors with anti-cancer properties.
    Biochemical pharmacology 11/2015; DOI:10.1016/j.bcp.2015.11.005 · 5.01 Impact Factor
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    • "HDACs together with histone lysine acetyltransferases (HATs) are responsible for the balance between acetylated/deacetylated states of histones, therefore transform the chromatin structure and alter gene transcription. Growing number of identified acetylated non-histone proteins demonstrate that reversible lysine acetylation also influence mRNA stability, and the localisation, interaction, degradation and function of non-histone proteins (Choudhary et al., 2009; Spange et al., 2009). HDAC inhibitors (HDACi) generally lead to growth arrest, differentiation and apoptosis of malignant cells, and have been extensively explored as potential anti-cancer agents (West & Johnstone, 2014). "
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    ABSTRACT: Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I and α -smooth muscle actin ( α -SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF- κ B1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.
    PeerJ 11/2015; 3:e1362. DOI:10.7717/peerj.1362 · 2.11 Impact Factor
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    • " antibodies as described previously ( Nallamilli et al . , 2014 ) . As a result , multiple major protein bands with molecular weight higher than histones were successfully detected ( Figure 2 ) , indicating that lysine acetylation not only happens to histones , but also occurs in non - histone proteins , which is consistent with previous reports ( Spange et al . , 2009 ; Nallamilli et al . , 2014 ) . Lysine acetylomes in plants were previously investigated by a number of researchers . Thus , Smith - Hammond et al . identified 664 acetylation sites in 358 proteins in pea seedling mitochondria ( Smith - Hammond et al . , 2014b ) . Moreover , in Arabidopsis thaliana , Wu et al . identified 64 acetylated "
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    ABSTRACT: Protein lysine acetylation is a reversible and dynamic post-translational modification. It plays an important role in regulating diverse cellular processes including chromatin dynamic, metabolic pathways, and transcription in both prokaryotes and eukaryotes. Although studies of lysine acetylome in plants have been reported, the throughput was not high enough, hindering the deep understanding of lysine acetylation in plant physiology and pathology. In this study, taking advantages of anti-acetyllysine-based enrichment and high-sensitive-mass spectrometer, we applied an integrated proteomic approach to comprehensively investigate lysine acetylome in strawberry. In total, we identified 1392 acetylation sites in 684 proteins, representing the largest dataset of acetylome in plants to date. To reveal the functional impacts of lysine acetylation in strawberry, intensive bioinformatic analysis was performed. The results significantly expanded our current understanding of plant acetylome and demonstrated that lysine acetylation is involved in multiple cellular metabolism and cellular processes. More interestingly, nearly 50% of all acetylated proteins identified in this work were localized in chloroplast and the vital role of lysine acetylation in photosynthesis was also revealed. Taken together, this study not only established the most extensive lysine acetylome in plants to date, but also systematically suggests the significant and unique roles of lysine acetylation in plants.
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