S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons

Nott, Alexi; Watson, P. Marc; Robinson, James D.; Crepaldi, Luca; Riccio, Antonella

doi:10.1038/nature07238

Cited by 379 publications

(353 citation statements)

References 33 publications

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“…S2A). Nuclear SNO-GAPDH transnitrosates SIRT1, HDAC2, and DNA-PK (DNAdependent protein kinase, catalytic subunit), impacting metabolic pathways, aging, and chromatin remodeling (41)(42)(43). HDAC2 was not detected in our SNO-proteome, although we observed elevated SNO-HDAC2 in CK-p25 mice by SNOTRAP-Western blot (Fig.…”

Section: S1mentioning

confidence: 40%

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

Seneviratne

Nott

Bhat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Protein S-nitrosation (SNO-protein), the nitric oxide-mediated posttranslational modification of cysteine thiols, is an important regulatory mechanism of protein function in both physiological and pathological pathways. A key first step toward elucidating the mechanism by which S-nitrosation modulates a protein's function is identification of the targeted cysteine residues. Here, we present a strategy for the simultaneous identification of SNO-cysteine sites and their cognate proteins to profile the brain of the CK-p25-inducible mouse model of Alzheimer's disease-like neurodegeneration. The approach-SNOTRAP (SNO trapping by triaryl phosphine)-is a direct tagging strategy that uses phosphine-based chemical probes, allowing enrichment of SNO-peptides and their identification by liquid chromatography tandem mass spectrometry. SNOTRAP identified 313 endogenous SNO-sites in 251 proteins in the mouse brain, of which 135 SNO-proteins were detected only during neurodegeneration. S-nitrosation in the brain shows regional differences and becomes elevated during early stages of neurodegeneration in the CK-p25 mouse. The SNO-proteome during early neurodegeneration identified increased S-nitrosation of proteins important for synapse function, metabolism, and Alzheimer's disease pathology. In the latter case, proteins related to amyloid precursor protein processing and secretion are S-nitrosated, correlating with increased amyloid formation. Sequence analysis of SNO-cysteine sites identified potential linear motifs that are altered under pathological conditions. Collectively, SNOTRAP is a direct tagging tool for global elucidation of the SNO-proteome, providing functional insights of endogenous SNO proteins in the brain and its dysregulation during neurodegeneration.S-nitrosation | Alzheimer's disease | secretase pathway | presenilin pathway | neurodegeneration P rotein S-nitrosation (SNO-protein), in which a cysteine (Cys) thiol is converted to a nitrosothiol (RSNO), is an important posttranslational modification (PTM). Cys residues targeted for S-nitrosation often impact enzyme activity, protein localization, and protein-protein interactions (1). SNO begins with the production of nitric oxide radicals (NO • ) via conversion of L-arginine to L-citrulline by nitric oxide synthase 1 (NOS1) (neuronal), NOS2 (inducible), and NOS3 (endothelial). NO-mediated SNO PTMs are thought to occur in vivo predominantly through radical recombination between NO • and a thiyl radical, transnitrosation by low-molecular weight NO carriers such as S-nitrosoglutathione (GSNO), or protein-assisted transnitrosation (2-8). In the healthy brain, low levels of NO and normal SNO PTMs play important roles in regulating synaptic plasticity, gene expression, and neuronal survival. In contrast, elevated NO levels associated with aging and environmental stress have been linked to neurological pathologies, including Alzheimer's (AD), Parkinson's, and Huntington's disease (9). AD is the most prevalent form of human dementia, with a frequency that progressiv...

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Section: S1mentioning

confidence: 40%

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

Seneviratne

Nott

Bhat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Our results concur with a recent mass spectrometry survey (42), which found HDAC1 and -2, but not HDAC8, among 417 cellular proteins modified by 100 M 4HNE (43). HDAC2 can also be nitrosylated at Cys 262 and Cys 274 (44,45). Because residues sensitive to ROS and reactive nitrogen species are often sensitive to modification by RCS, our results suggest that the homologous cysteine residues in HDAC1 and HDAC3 as well as yeast RPD3 could be sensitive to nitrosylation and oxidation.…”

Section: Discussionmentioning

confidence: 70%

Redox Signaling, Alkylation (Carbonylation) of Conserved Cysteines Inactivates Class I Histone Deacetylases 1, 2, and 3 and Antagonizes Their Transcriptional Repressor Function

Doyle

Fitzpatrick

2010

Journal of Biological Chemistry

128

107

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Cells use redox signaling to adapt to oxidative stress. For instance, certain transcription factors exist in a latent state that may be disrupted by oxidative modifications that activate their transcription potential. We hypothesized that DNA-binding sites (response elements) for redox-sensitive transcription factors may also exist in a latent state, maintained by co-repressor complexes containing class I histone deacetylase (HDAC) enzymes, and that HDAC inactivation by oxidative stress may antagonize deacetylase activity and unmask electrophile-response elements, thus activating transcription. Electrophiles suitable to test this hypothesis include reactive carbonyl species, often derived from peroxidation of arachidonic acid. We report that ␣,␤-unsaturated carbonyl compounds, e.g. the cyclopentenone prostaglandin, 15-deoxy-⌬12,14-PGJ 2 (15d-PGJ 2 ), and 4-hydroxy-2-nonenal (4HNE), alkylate (carbonylate), a subset of class I HDACs including HDAC1, -2, and -3, but not HDAC8. Covalent modification at two conserved cysteine residues, corresponding to Cys 261 and Cys 273 in HDAC1, coincided with attenuation of histone deacetylase activity, changes in histone H3 and H4 acetylation patterns, derepression of a LEF1⅐␤-catenin model system, and transcription of HDAC-repressed genes, e.g. heme oxygenase-1 (HO-1), Gadd45, and HSP70. Identification of particular class I HDACs as components of the redox/ electrophile-responsive proteome offers a basis for understanding how cells stratify their responses to varying degrees of pathophysiological oxidative stress associated with inflammation, cancer, and metabolic syndrome.Cellular oxidative stress can vary widely in severity and scope. Consequently, redox signaling must accommodate physiological demands from respiration, metabolism, host defense, cell replication, and aging plus demands from pathological oxidative stress encountered during inflammation, malignancy, reperfusion injury, and metabolic syndrome. Stimulus-response coupling in these different situations must be properly stratified; otherwise, maladaptation can have grave outcomes. An insufficient response to oxidative stress can lead to cell death, which typifies many neurodegenerative diseases. An excessive response to oxidative stress can lead to hypertrophy, hyperplasia, or neoplasia (1).Phenotypic adaptation to oxidative stress derives, in part, from the expression of genes to protect cells from damage, to repair damage, and to bolster their survival. This involves cellular proteins collectively termed the redox/electrophile-responsive proteome (2, 3). These proteins vary widely in cellular localization and functionality, but all have cysteine residues with distinctively nucleophilic thiols (pK a Յ 5), which are readily oxidized to sulfenic/sulfinic acids by reactive oxygen species (ROS) 2 or readily alkylated by reactive carbonyl species (RCS) (4, 5). RCS originate from either non-enzymatic or enzymatic peroxidation of lipids (especially arachidonic acid), which generates ␣,␤-unsaturated aldehydes (enals) (e.g....

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“…One possibility is that HDAC2 is distinct from other HDAC members by post-translational modifications. It has been shown that HDAC2 protein is regulated by lysine ubiquitination, serine phosphorylation, tyrosine nitration, and cysteine nitrosylation (Sun et al 2002;Kramer et al 2003;Nott et al 2008;Adenuga et al 2009;Brandl et al 2009;Osoata et al 2009). Other ubiquitin conjugation and ligation enzymes have also been implicated in HDAC2 destruction.…”

Section: Discussionmentioning

confidence: 99%

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

Zhang¹,

Kan²,

Huang³

et al. 2011

Genes Dev.

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Histone deacetylases (HDACs) are major epigenetic modulators involved in a broad spectrum of human diseases including cancers. Administration of HDAC inhibitors (HDACis) leads to growth inhibition, differentiation, and apoptosis of cancer cells. Understanding the regulatory mechanism of HDACs is imperative to harness the therapeutic potentials of HDACis. Here we show that HDACi-and DNA damage-induced apoptosis are severely compromised in mouse embryonic fibroblasts lacking a HECT domain ubiquitin ligase, Mule (Mcl-1 ubiquitin ligase E3). Mule specifically targets HDAC2 for ubiquitination and degradation. Accumulation of HDAC2 in Mule-deficient cells leads to compromised p53 acetylation as well as crippled p53 transcriptional activation, accumulation, and apoptotic response upon DNA damage and Nutlin-3 treatments. These defects in Mule-null cells can be partially reversed by HDACis and fully rescued by lowering the elevated HDAC2 in Mule-null cells to the normal levels as in wild-type cells. Taken together, our results reveal a critical regulatory mechanism of HDAC2 by Mule and suggest this pathway determines the cellular response to HDACis and DNA damage.

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S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons

Cited by 379 publications

References 33 publications

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

Redox Signaling, Alkylation (Carbonylation) of Conserved Cysteines Inactivates Class I Histone Deacetylases 1, 2, and 3 and Antagonizes Their Transcriptional Repressor Function

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

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