Proteome-wide acetylation dynamics in human cells

Kori, Yekaterina; Sidoli, Simone; Yuan, Zuo Fei; Lund, Peder J.; Zhao, Xiaolu; Garcia, Benjamin A.

doi:10.1038/s41598-017-09918-3

Cited by 43 publications

(46 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…If the correlation is linear and positive, a possible biological interpretation of the data is that the acetyl-CoA levels change affecting the abundance of histone acetylation (Figure 5F). An example of this analysis is illustrated in [36]…”

Section: Methodsmentioning

confidence: 99%

Integrated Analysis of Acetyl-CoA and Histone Modification via Mass Spectrometry to Investigate Metabolically Driven Acetylation

Trefely

Garcia

Carrer

2019

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

Summary Acetylation is a highly abundant and dynamic post-translational modification (PTM) on histone proteins which, when present on chromatin bound histones, facilitates the accessibility of DNA for gene transcription. The central metabolite, acetyl-CoA, is a substrate for acetyltransferases, which catalyze protein acetylation. Acetyl-CoA is an essential intermediate in diverse metabolic pathways, and cellular acetyl-CoA levels fluctuate according to extracellular nutrient availability and the metabolic state of the cell. The Michaelis constant (Km) of most histone acetyltransferases (HATs), which specifically target histone proteins, fall within the range of cellular acetyl-CoA concentrations. As a consequence, global levels of histone acetylation are often restricted by availability of acetyl-CoA. Such metabolic regulation of histone acetylation is important for cell proliferation, differentiation and a variety of cellular functions. In cancer, numerous oncogenic signaling events hijack cellular metabolism, ultimately inducing an extensive rearrangement of the epigenetic state of the cell. Understanding metabolic control of the epigenome through histone acetylation is essential to illuminate the molecular mechanisms by which cells sense, adapt and occasionally disengage nutrient fluctuations and environmental cues from gene expression. In particular, targeting metabolic regulators or even dietary interventions to impact acetyl-CoA availability and histone acetylation is a promising target in cancer therapy. Liquid chromatography coupled to mass spectrometry (LC-MS) is the most accurate methodology to quantify protein PTMs and metabolites. In this chapter, we present state-of-the-art protocols to analyze histone acetylation and acetyl-CoA. Histones are extracted and digested into short peptides (4–20 aa) prior to LC-MS. Acetyl-CoA is extracted from cells and analyzed using an analogous mass spectrometry-based procedure. Model systems can be fed with isotopically labeled substrates to investigate the metabolic preference for acetyl-CoA production and the metabolic dependence and turnover of histone acetylation. We also present an example of data integration to correlate changes in acetyl-CoA production with histone acetylation.

show abstract

Section: Methodsmentioning

confidence: 99%

Integrated Analysis of Acetyl-CoA and Histone Modification via Mass Spectrometry to Investigate Metabolically Driven Acetylation

Trefely

Garcia

Carrer

2019

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Comparison of the datasets allowed to identify and distinguish ISGylated sites from ubiquitin sites in vivo (Zhang et al, 2019). Similar approaches have already been used in several cell systems to identify different post-translational modifications such as, phosphorylation (Rush et al, 2005), ubiquitination (Xu et al, 2010a;Kim et al, 2011), acetylation (Weinert et al, 2011;Kori et al, 2017), methylation and SUMOylation (Impens et al, 2014;Lamoliatte et al, 2017).…”

Section: Identification Of Isg15 Substratesmentioning

confidence: 99%

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

2020

View full text Add to dashboard Cite

The interferon (IFN)-stimulated gene product 15 (ISG15) represents an ubiquitin-like protein (Ubl), which in a process termed ISGylation can be covalently linked to target substrates via a cascade of E1, E2, and E3 enzymes. Furthermore, ISG15 exerts functions in its free form both, as an intracellular and as a secreted protein. In agreement with its role as a type I IFN effector, most functions of ISG15 and ISGylation are linked to the anti-pathogenic response. However, also key roles in other cellular processes such as protein translation, cytoskeleton dynamics, exosome secretion, autophagy or genome stability and cancer were described. Ubiquitin-specific protease 18 (USP18) constitutes the major ISG15 specific protease which counteracts ISG15 conjugation. Remarkably, USP18 also functions as a critical negative regulator of the IFN response irrespective of its enzymatic activity. Concordantly, lack of USP18 function causes fatal interferonopathies in humans and mice. The negative regulatory function of USP18 in IFN signaling is regulated by various protein-protein interactions and its stability is controlled via proteasomal degradation. The broad repertoire of physiological functions and regulation of ISG15 and USP18 offers a variety of potential intervention strategies which might be of therapeutic use. Due to the high mutation rates of pathogens which are often species specific and constantly give rise to a variety of immune evasion mechanisms, immune effector systems are under constant evolutionarily pressure. Therefore, it is not surprising that considerable differences in ISG15 with respect to function and sequence exist even among closely related species. Hence, it is essential to thoroughly evaluate the translational potential of results obtained in model organisms especially for therapeutic strategies. This review covers existing and conceptual assay systems to target and identify modulators of ISG15, ISGylation, USP18 function, and protein-protein interactions within this context. Strategies comprise mouse models for translational perspectives, cell-based and biochemical assays as well as chemical probes.

show abstract

“…One prerequisite of BER is the accessibility of the DNA, which requires reorganization of chromatin with histone acetylation processes near damaged sites. In this context, DNA damage‐mediated histone acetylation can enhance consumption of nuclear acetyl CoA which is in large parts derived from glucose . This process could contribute, at least in a small proportion, to UVA‐enhanced glucose consumption.…”

Section: The Immediate Effects Of Uva Damage and Its Metabolic Changementioning

confidence: 99%

UVA, metabolism and melanoma: UVA makes melanoma hungry for metastasis

Kamenisch

Ivanova

Drexler

et al. 2018

Experimental Dermatology

View full text Add to dashboard Cite

Ultraviolet (UV) radiation has a plethora of effects on human tissues. In the UV spectrum, wavelengths above 320 nm fall into the UVA range, and for these, it has been shown that they induce reactive oxygen species (ROS), DNA mutations and are capable to induce melanoma in mice. In addition to this, it was recently shown that UVA irradiation and UVA-induced ROS also increase glucose metabolism of melanoma cells. UVA irradiation causes a persistent increase in glucose consumption, accompanied by increased glycolysis, increased lactic acid production and activation of the pentose phosphate pathway. Furthermore, it was shown that the enhanced secretion of lactic acid is important for invasion of melanoma in vitro. The current knowledge of this link between UVA, metabolism and melanoma, possible mechanisms of UVA-induced glucose metabolism and their starting points are discussed in this review with focus on ROS- and UVA-induced cellular stress signalling, DNA damage signalling and DNA repair systems. When looking at the benefits of UVA-induced glucose metabolism, it becomes apparent that there are more advantages of these metabolic changes than one would expect. Besides the role of lactic acid as initiator of protease expression and invasion, its role for immune escape of melanoma cells and the pentose phosphate pathway-derived nicotinamide adenine dinucleotide phosphate (NADPH) as part of a ROS detoxification strategy are discussed.

show abstract

Proteome-wide acetylation dynamics in human cells

Cited by 43 publications

References 56 publications

Integrated Analysis of Acetyl-CoA and Histone Modification via Mass Spectrometry to Investigate Metabolically Driven Acetylation

Integrated Analysis of Acetyl-CoA and Histone Modification via Mass Spectrometry to Investigate Metabolically Driven Acetylation

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

UVA, metabolism and melanoma: UVA makes melanoma hungry for metastasis

Contact Info

Product

Resources

About