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AP-MS analysis of sirtuin-2 interactions and whole-cell proteome analysis in human fibroblasts

ABSTRACT: Sirtuins are NAD+-dependent deacylases with diverse enzymatic activities and substrates. They were implicated in regulation of cancer progression, neurodegeneration, aging, and viral infection. Sirtuin-2 localizes to the cytoplasm and is known to deacetylate alpha-tubulin. Current knowledge on sirtuin-2 interactions and its effect on gene expression in normal cells is very limited. We used proteomics approach to define its interactions and its effect on global protein levels in human fibroblasts.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Fibroblast

SUBMITTER: Hanna Budayeva

LAB HEAD: Ileana M. Cristea

PROVIDER: PXD004212 | Pride | 2016-08-12

REPOSITORIES: Pride

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			Action	DRS
	010616_IDIRT_E1.raw	Raw
	010616_IDIRT_E2.raw	Raw
	010616_IDIRT_E3.raw	Raw
	010616_IDIRT_SIRT2H_WTL.msf	Msf
	011014_SIRT2-EGFP.msf	Msf

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Publications

Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking.

Budayeva Hanna G HG Cristea Ileana M IM

Molecular & cellular proteomics : MCP 20160808 10

Human sirtuin 2 (SIRT2) is an NAD<sup>+</sup>-dependent deacetylase that primarily functions in the cytoplasm, where it can regulate α-tubulin acetylation levels. SIRT2 is linked to cancer progression, neurodegeneration, and infection with bacteria or viruses. However, the current knowledge about its interactions and the means through which it exerts its functions has remained limited. Here, we aimed to gain a better understanding of its cellular functions by characterizing SIRT2 subcellular loc ...[more]

PMID: 27503897

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Sirtuin 2 Promotes HCMV Replication by Regulating Cell Cycle Progression

Project description:The host cell cycle is a major target for manipulation by viral pathogens, which often replicate in certain cell cycle stages. The prevalent pathogen human cytomegalovirus (HCMV), for instance, only replicates during G1 and therefore employs diverse mechanisms for regulating cell cycle progression. Here, we demonstrate that the human enzyme sirtuin 2 (SIRT2) is required for HCMV-mediated cell cycle dysregulation. By combining virology assays with mass pectrometry-based proteome, acetylome, and interactome analyses, we have defined a pro-virus function for SIRT2 in regulating the G1 to S phase transition.

2023-10-13 | PXD041171 | Pride

Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction by inhibiting sirtuin mediated deacetylation

Project description:Perturbed metabolism of ammonia, an endogenous cytotoxic molecule, causes mitochondrial dysfunction with decreased nicotinamide adenine dinucleotide (NAD+) in skeletal muscle. Consistent with our previous report of enrichment of NAD metabolism and sirtuin pathways during hyperammonemia, NAD+-dependent Sirtuin3 (Sirt3) expression and deacetylase activity weredecreased with increased muscle protein acetylation in murine and human skeletal muscle/myotubes. Acetylomics and cell fractions showed hyperammonemia-induced hyperacetylation of critical mitochondrial and signaling molecules. Overexpression of mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) reversed ammonia-induced oxidative dysfunction, electron transport chain (ETC) supercomplex disassembly, lower ATP content, NAD+, and redox ratio (NAD+/NADH). Protein hyperacetylation, post-mitotic senescence and lower mitochondrial sirtuin (Sirt3) expressionduring hyperammonemia were also reversed by MitoLbNOX. Sirt3 overexpression alone did not reverse ammonia-induced redox or mitochondrial dysfunction but reversed hyperacetylation and senescence. These data show that targeting redox ratio, rather than Sirt3, more consistently restores mitochondrial homeostasis and protein acetylation during hyperammonemia.

2023-10-24 | PXD033430 | Pride

Genome-wide Analysis of Functional Sirtuin Chromatin Targets in Yeast

Project description:Sir2 and the homologous proteins, Hst1, Hst2, Hst3, and Hst4 from Saccharomyces cerevisiae are NAD+-dependent histone deacetylases of the sirtuin protein family. Sir2 functions in transcriptional silencing at the silent mating-type loci, telomeres, and rDNA locus, but also promotes replicative lifespan. To gain a better understanding of the chromatin-regulatory roles carried out by Sir2 and the Hst proteins, we performed ChIP-sequencing analysis on all five sirtuins and Sum1, the DNA binding partner for Hst1. Sir2, Hst1, and Sum1 were abundantly, and functionally co-enriched at several major targets, including the telomeric repeats, where they were required for maintaining proper telomere repeat length. At tRNA target genes they were required for efficient cohesin and condensin deposition. Across the open reading frames of glycolytic and ribosomal protein genes, Sir2 and Hst1 functioned in NAD+-dependent transcriptional repression at the diauxic shift, directly linking Sir2 to glucose metabolism, which could have implications for longevity. Six factors and Input ChIP-seq samples were analyzed in Saccharomyces eerevisiae.

2013-05-10 | E-GEOD-41415 | biostudies-arrayexpress

Sustained activation of AMPK enhances differentiation of human iPSC-derived cardiomyocytes via sirtuin activation

Project description:Lee and colleagues demonstrate that sustained activation of AMPK enhances differentiation of iPSC-derived cardiomyocytes. Sustained AMPK activation decreased histone acetylation at known target sites for nuclear-localized sirtuins, suggesting that AMPK activation enhances sirtuin activity. AMPK-induced sirtuin-mediated deacetylation of histone proteins may regulate chromatin accessibility and enhance cardiomyocyte differentiation.

2020-06-12 | GSE152265 | GEO

The function of sirtuin family in NER

Project description:The role of sirtuin family in regulating DNA DSB repair has been extensively investigated, and here, we explore the molecular mechanisms of Sirtuin family in nucleotide excision repair.

2020-08-04 | PXD020721 |

Cap analysis gene expression (CAGE) of Aspergillus luchuensis mut. kawachii control and sirtuin D disruptant strains

Project description:Sirtuin is considered to play a significant role in the growth phase-dependent gene expression. In this study, we characterized sirtuin in the white koji fungus, Aspergillus kawachii, to examine their role on regulation of amylolytic enzymes and citric acid productions during the solid-state culture (koji). Characterization of rice-koji made using five putative sirtuin gene disruptants indicated that they are involved in amylolytic activity and acidity of rice koji; especially the sirD disruptant showed lower levels of α-amylase activity and citric acid production per mycelial weight in the koji compared the control strain. In addition, the sirD disruptant also showed a change in mycelial pigmentation, higher sensitivity to cell wall biogenesis inhibitor such as calcofluor white and Congo red, and reduced conidia formation, indicating that SirD is required for secondary metabolism, cell wall integrity, and conidial development. The cap analysis gene expression (CAGE) indicated that the transcriptional changes related to the characteristic phenotype of the sirD disruptant (e.g., a reduced transcript level of acid-stable α-amylase gene and a citric acid exporter) in rice koji. These results indicated that SirD has a significant role on the global transcriptional regulation including productions of α-amylase and citric acid in A. kawachii during the solid-state fermentation process.

2019-06-15 | GSE132729 | GEO

Telomere dysfunction induces Sirtuin repression that drives telomere-dependent disease

Project description:Telomere dysfunction induces Sirtuin repression that drives telomere-dependent disease

| PRJNA517700 | ENA

Accurate quantification of site-specific acetylation stoichiometry reveals the impact of sirtuin deacetylase CobB on the E. coli acetylome

Project description:We applied SD-SILAC to determine absolute acetylation stoichiometry in exponentially-growing and stationary-phase wild type and sirtuin deacetylase CobB-deficient E. coli. We further assayed stoichiometry in phophotransacetylase (pta) and acetate kinase (ackA) mutant strains in the presence and absence of the sirtuin inhibitor nicotinamide. Comparison to relative quantification under the same conditions validated our stoichiometry estimates at hundreds of sites, demonstrating the accuracy of our method. We measured acetylation stoichiometry at 3,669 unique sites and found that the vast majority of acetylation occurs at very low stoichiometry (median 0.04%). Manipulations that cause increased nonenzymatic acetylation by acetyl-phosphate (AcP), such stationary-phase arrest and deletion of ackA, resulted in globally increased acetylation stoichiometry. Similar to sirtuin deacetylase 3 (SIRT3) in mitochondria, CobB suppressed acetylation to lower than median stoichiometry at hundreds of sites in WT, pta, and ackA cells. These results suggest an evolutionarily conserved function of sirtuin deacetylases in suppressing low stoichiometry acetylation.

2017-03-07 | PXD005757 | Pride

Legionella pneumophila infection rewires the Acanthamoeba castellanii transcriptome, highlighting a class of sirtuin genes

Project description:Through RNA-sequencing we compared A. castellanii infected with wild type L. pneumophila to A. castellanii infected with an isogenic dotA mutant strain, which is unable to replicate intracellularly. We identified clear morphological and transcriptional changes in A. castellanii over the course of infection. Genes differentially expressed during infection fell into fundamental biological processes, such as small GTPase signalling, cytoskeleton dynamics, metabolism and cell proliferation. Members of the Sirtuin family of class III histone deacetylases were upregulated by A. castellanii throughout wild type L. pneumophila infection. sir6f expression was important for A. castellanii proliferation during infection and L. pneumophila replication

2020-07-11 | GSE154179 | GEO

Genome-wide Analysis of Functional Sirtuin Chromatin Targets in Yeast

2013-05-10 | GSE41415 | GEO