Time line of redox events in aging postmitotic cells

Brandes, Nicolas; Tienson, Heather L.; Lindemann, Antje; Vitvitsky, Victor; Reichmann, Dana; Banerjee, Ruma; Jakob, Ursula

doi:10.7554/elife.00306

Cited by 69 publications

(113 citation statements)

References 45 publications

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“…It was found that the yeast cells underwent a significant increase in global oxidation (i.e. ϳ80% of the 300 proteins) several days before they died (40). A similar phenomenon was also observed during the lifespan of C. elegans, as the aged worms had significantly more oxidized protein thiols than young adults (41).…”

Section: The Expanding Landscape Of the Thiol Redox Proteomementioning

confidence: 55%

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The Expanding Landscape of the Thiol Redox Proteome

Yang

Carroll

Liebler

2016

Molecular & Cellular Proteomics

184

111

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Cysteine occupies a unique place in protein chemistry. The nucleophilic thiol group allows cysteine to undergo a broad range of redox modifications beyond classical thiol-disulfide redox equilibria, including S-sulfenylation (-SOH), S-sulfinylation (-SO 2 H), S-sulfonylation (-SO 3 H), S-nitrosylation (-SNO), S-sulfhydration (-SSH), S-glutathionylation (-SSG), and others. Emerging evidence suggests that these post-translational modifications (PTM) are important in cellular redox regulation and protection against oxidative damage. Identification of protein targets of thiol redox modifications is crucial to understanding their roles in biology and disease. However, analysis of these highly labile and dynamic modifications poses challenges. Recent advances in the design of probes for thiol redox forms, together with innovative mass spectrometry based chemoproteomics methods make it possible to perform global, site-specific, and quantitative analyses of thiol redox modifications in complex proteomes.

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Section: The Expanding Landscape Of the Thiol Redox Proteomementioning

confidence: 55%

“…These studies established a clear connection between the thiol oxidation statues and aging in S. cerevisiae and C.elegans (40,41). It was found that the yeast cells underwent a significant increase in global oxidation (i.e.…”

Section: The Expanding Landscape Of the Thiol Redox Proteomementioning

confidence: 85%

The Expanding Landscape of the Thiol Redox Proteome

Yang

Carroll

Liebler

2016

Molecular & Cellular Proteomics

184

111

View full text Add to dashboard Cite

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“…In the past, formations of cysteine S-sulphenic acids on proteins were detected indirectly, through measurement of cysteine reactivities toward hydrogen peroxide (H 2 O 2 ). Accordingly, proteomic techniques for large-scale redox profiling of cysteine oxidative modifications employed indirect analyses based on differential labeling of protein thiols 16–25 . These techniques rely on high concentrations of thiol alkylating reagents, which may react with protein S-sulphenic acids as well 26, 27 .…”

Section: Introductionmentioning

confidence: 99%

Global, in situ, site-specific analysis of protein S-sulfenylation

et al. 2015

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Protein S-sulphenylation is the reversible oxidative modification of cysteine thiol groups to form cysteine S-sulphenic acids. Mapping the specific sites of protein S-sulphenylation onto complex proteomes is crucial to understanding the molecular mechanisms controlling redox signaling and regulation. This protocol describes global, in situ, site-specific analysis of protein S-sulphenylation using sulphenic acid-specific chemical probes and mass spectrometry-based proteomics. The major steps in this protocol are (1) optimization of conditions for selective labeling of cysteine S-sulphenic acids in intact cells with the commercially available dimedone-based probe, DYn-2, (2) tagging the modified cysteines with a functionalized biotin reagent containing a cleavable linker via Cu(I)-catalyzed azide-alkyne cycloaddition reaction, (3) enrichment of the biotin-tagged tryptic peptides with streptavidin, (4) liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based shotgun proteomics and (5) computational data analysis. We also outline strategies for quantitative analysis of this modification in cells responding to redox perturbations and discuss special issues pertaining to experimental design of thiol redox studies. Our chemoproteomic platform should be broadly applicable to the investigation of other bioorthogonal-chemically engineered posttranslational modifications. The entire analysis protocol takes about 1 week to complete.

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“…In particular, it has been shown that levels of NADPH and NAD + decline upon yeast aging, but NADPH levels are maintained when yeast cells are starved [65]–[67]. Decline in NAD + levels with aging were also reported in mice [68].…”

Section: Resultsmentioning

confidence: 99%

Deteriorated Stress Response in Stationary-Phase Yeast: Sir2 and Yap1 Are Essential for Hsf1 Activation by Heat Shock and Oxidative Stress, Respectively

et al. 2014

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Stationary-phase cultures have been used as an important model of aging, a complex process involving multiple pathways and signaling networks. However, the molecular processes underlying stress response of non-dividing cells are poorly understood, although deteriorated stress response is one of the hallmarks of aging. The budding yeast Saccharomyces cerevisiae is a valuable model organism to study the genetics of aging, because yeast ages within days and are amenable to genetic manipulations. As a unicellular organism, yeast has evolved robust systems to respond to environmental challenges. This response is orchestrated largely by the conserved transcription factor Hsf1, which in S. cerevisiae regulates expression of multiple genes in response to diverse stresses. Here we demonstrate that Hsf1 response to heat shock and oxidative stress deteriorates during yeast transition from exponential growth to stationary-phase, whereas Hsf1 activation by glucose starvation is maintained. Overexpressing Hsf1 does not significantly improve heat shock response, indicating that Hsf1 dwindling is not the major cause for Hsf1 attenuated response in stationary-phase yeast. Rather, factors that participate in Hsf1 activation appear to be compromised. We uncover two factors, Yap1 and Sir2, which discretely function in Hsf1 activation by oxidative stress and heat shock. In Δyap1 mutant, Hsf1 does not respond to oxidative stress, while in Δsir2 mutant, Hsf1 does not respond to heat shock. Moreover, excess Sir2 mimics the heat shock response. This role of the NAD+-dependent Sir2 is supported by our finding that supplementing NAD+ precursors improves Hsf1 heat shock response in stationary-phase yeast, especially when combined with expression of excess Sir2. Finally, the combination of excess Hsf1, excess Sir2 and NAD+ precursors rejuvenates the heat shock response.

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Time line of redox events in aging postmitotic cells

Cited by 69 publications

References 45 publications

The Expanding Landscape of the Thiol Redox Proteome

The Expanding Landscape of the Thiol Redox Proteome

Global, in situ, site-specific analysis of protein S-sulfenylation

Deteriorated Stress Response in Stationary-Phase Yeast: Sir2 and Yap1 Are Essential for Hsf1 Activation by Heat Shock and Oxidative Stress, Respectively

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