Proteome-wide Changes in Protein Turnover Rates in C. elegans Models of Longevity and Age-Related Disease

Visscher, Marieke; Henau, Sasha De; Wildschut, Mattheus H.E.; Es, Robert J.J. van; Dhondt, Ineke; Michels, Helen; Kemmeren, Patrick; Nollen, Ellen A. A.; Braeckman, Bart P.; Burgering, Boudewijn M.T.; Vos, Harmjan R.; Dansen, Tobias B.

doi:10.1016/j.celrep.2016.08.025

Cited by 56 publications

(58 citation statements)

References 31 publications

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“…Only three proteins (CPN-3, ASP-4, and VIT-6) display marginally significant higher turnover rates in daf-2 , but they lack a clear biological relationship. This dramatic change in protein turnover in long-lived daf-2 was also observed in a parallel study (Visscher et al, 2016 [this issue of Cell Reports ]).…”

Section: Discussionsupporting

confidence: 74%

FOXO/DAF-16 Activation Slows Down Turnover of the Majority of Proteins in C. elegans

et al. 2016

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SummaryMost aging hypotheses assume the accumulation of damage, resulting in gradual physiological decline and, ultimately, death. Avoiding protein damage accumulation by enhanced turnover should slow down the aging process and extend the lifespan. However, lowering translational efficiency extends rather than shortens the lifespan in C. elegans. We studied turnover of individual proteins in the long-lived daf-2 mutant by combining SILeNCe (stable isotope labeling by nitrogen in Caenorhabditis elegans) and mass spectrometry. Intriguingly, the majority of proteins displayed prolonged half-lives in daf-2, whereas others remained unchanged, signifying that longevity is not supported by high protein turnover. This slowdown was most prominent for translation-related and mitochondrial proteins. In contrast, the high turnover of lysosomal hydrolases and very low turnover of cytoskeletal proteins remained largely unchanged. The slowdown of protein dynamics and decreased abundance of the translational machinery may point to the importance of anabolic attenuation in lifespan extension, as suggested by the hyperfunction theory.

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Section: Discussionsupporting

confidence: 74%

FOXO/DAF-16 Activation Slows Down Turnover of the Majority of Proteins in C. elegans

et al. 2016

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“…4k). The translation rate was defined as the time needed for half of each quantified protein to be labeled with the given SILAC label 50 . At the global level, FMR1 expression resulted in global translational inhibition compared with the expression of FMR1-I304N (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The time it took for half the protein to be labeled (THPL) was calculated for all identified proteins as described by Visscher et al 50 . In short, we performed a linear regression between the log-transformed fraction of labeled protein and the pulse time.…”

Section: Methodsmentioning

confidence: 99%

“…We then extrapolated the THPL by dividing the slope of the regression by log(0.5). In addition to the four pulsed time points, we forced the regression lines though zero as described previously 50 . To ensure high confidence of our individual THPL measurements, we used only the proteins with an identified label ratio in all time points and a Pearson correlation coefficient of 0.95 or higher for downstream analyses.…”

Section: Methodsmentioning

confidence: 99%

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N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

Edupuganti

Geiger

Lindeboom

et al. 2017

Nat Struct Mol Biol

438

453

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RNA modifications are integral to the regulation of RNA metabolism. One abundant mRNA modification is N6-methyladenosine (m6A), which affects various aspects of RNA metabolism, including splicing, translation and degradation. Current knowledge about the proteins recruited to m6A to carry out these molecular processes is still limited. Here we describe comprehensive and systematic mass-spectrometry-based screening of m6A interactors in various cell types and sequence contexts. Among the main findings, we identified G3BP1 as a protein that is repelled by m6A and positively regulates mRNA stability in an m6A-regulated manner. Furthermore, we identified FMR1 as a sequence-context-dependent m6A reader, thus revealing a connection between an mRNA modification and an autism spectrum disorder. Collectively, our data represent a rich resource and shed further light on the complex interplay among m6A, m6A interactors and mRNA homeostasis.

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“…Hence, a reduction-of-function mutation in these pathways, such as daf-2(e1370), is indeed expected to decrease anabolic processes such as protein synthesis. This was recently confirmed using classical 35 S pulse chase labelling and stable isotope labelling combined with mass spectrometry Visscher et al, 2016). About half of the protein species show decreased turnover rates in the long-lived daf-2 mutants, while turnover of the other proteins remains unchanged .…”

Section: Damage Clearance and Protein Turnovermentioning

confidence: 70%

Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

Braeckman

Dhondt

2017

Nematol

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Summary -The insulin/IGF-1 signalling (IIS) pathway connects nutrient levels to metabolism, growth and lifespan in eukaryotes ranging from yeasts to humans, including nematodes such as the genetic model organism Caenorhabditis elegans. The link between ageing and the IIS pathway has been thoroughly studied in C. elegans; upon reduced IIS signalling, a genetic survival program is activated resulting in a drastic lifespan extension. One of the components of this program is the upregulation of antioxidant activity but experiments failed to show a clear causal relation to longevity. However, oxidative damage, such as protein carbonyls, accumulates at a slower pace in long-lived C. elegans mutants with reduced IIS. This is probably not achieved by increased macroautophagy, a process that sequesters cellular components to be eliminated as protein turnover rates are slowed down in IIS mutants. The IIS mutant daf-2, bearing a mutation in the insulin/IGF-1 receptor, recapitulates the dauer survival program, including accumulation of fat and glycogen. Fat can be converted into glucose and glycogen via the glyoxylate shunt, a pathway absent in vertebrates. These carbohydrates can be used as substrates for trehalose synthesis, also absent in mammals. Trehalose, a non-reducing homodimer of glucose, stabilises intracellular components and is responsible for almost half of the lifespan extension in IIS mutants. Hence, the molecular mechanisms by which lifespan is extended under reduced IIS may differ substantially between phyla that have an active glyoxylate cycle and trehalose synthesis, such as ecdysozoans and fungi, and vertebrate species such as mammals.

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Proteome-wide Changes in Protein Turnover Rates in C. elegans Models of Longevity and Age-Related Disease

Cited by 56 publications

References 31 publications

FOXO/DAF-16 Activation Slows Down Turnover of the Majority of Proteins in C. elegans

FOXO/DAF-16 Activation Slows Down Turnover of the Majority of Proteins in C. elegans

N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

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