Abstract
Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS-inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature-dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS.
Highlights
There is increasing evidence that reactive oxygen species (ROS) play diverse roles in normal physiology and disease
Our discovery that PRDX-2 is required for insulin secretion reveals a new physiological role for a peroxiredoxin, as well as provides an explanation for the unexpected role of this peroxidase in limiting C. elegans stress resistance
PRDX-2 is required for insulin/IGF-1-like signalling (IIS)-dependent inhibition of SKN-1
Summary
There is increasing evidence that reactive oxygen species (ROS) play diverse roles in normal physiology and disease. The thioredoxin peroxidase activity of the yeast homologue of Prdx, TSA1, is required for the increased replicative lifespan associated with caloric restriction (Molin et al, 2011). Cytosolic 2-Cys Prx (Prdx and Prdx2), orthologous to TSA1 in yeast, have been shown to have nonredundant biological functions, for example in preventing the development of malignant tumours and supporting the production and maintenance of red blood cells in mice (Lee et al, 2003; Neumann et al, 2003; Rhee & Woo, 2011). Functional redundancy between Prdx and Prdx has prevented the detailed examination of how these Prx affect mammalian physiology and the development of age-associated diseases
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