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RPN-6 determines C. elegans longevity under proteotoxic stress conditions

Abstract

Organisms that protect their germ-cell lineages from damage often do so at considerable cost: limited metabolic resources become partitioned away from maintenance of the soma, leaving the ageing somatic tissues to navigate survival amid an environment containing damaged and poorly functioning proteins. Historically, experimental paradigms that limit reproductive investment result in lifespan extension. We proposed that germline-deficient animals might exhibit heightened protection from proteotoxic stressors in somatic tissues. We find that the forced re-investment of resources from the germ line to the soma in Caenorhabditis elegans results in elevated somatic proteasome activity, clearance of damaged proteins and increased longevity. This activity is associated with increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders.

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Figure 1: Germline-lacking nematodes have increased proteasome activity.
Figure 2: DAF-16 is required for proteasome activity in glp-1(e2141) mutant nematodes.
Figure 3: DAF-16 is necessary for increased expression of rpn-6.1 in glp-1 mutants.
Figure 4: rpn-6.1 is a determinant of stress resistance and viability.
Figure 5: rpn-6.1 protects from polyglutamine aggregation.

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Acknowledgements

We thank S. Panowski for help with the generation of transgenic strains. We thank D. Joyce for proteasome activity assays and S. Wolff for comments on the manuscript. This work was supported by HHMI and the NIA. D.V. was a recipient of the F.M. Kirby, Inc. Foundation Postdoctoral Scholar Award and Beatriu de Pinós (AGAUR) fellowship.

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Contributions

D.V. and A.D. planned and supervised the project. D.V. performed the experiments, data analysis and interpretation. I.M. performed biochemistry experiments and contributed to other assays. Z.L. performed UPS reporter experiment, lifespans and injections. P.M.D. performed the filter trap assay. C.M. performed immunoblots. A.P.C.R. and G.M. performed the transcription factor binding site analysis. The manuscript was written by D.V. and A.D. and edited by I.M. and C.M. All authors discussed the results and commented on the manuscript.

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Correspondence to Andrew Dillin.

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Vilchez, D., Morantte, I., Liu, Z. et al. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489, 263–268 (2012). https://doi.org/10.1038/nature11315

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