The 1-Cys peroxiredoxin, PRDX-6, suppresses a pro-survival response, including the Flavin monoxygenase, FMO-2, that protects against fungal and bacterial infection

Abstract

Reactive oxygen species (ROS)-induced cell damage contributes to many diseases. However, ROS also contribute to cell signaling and immune defences. As ubiquitous thiol peroxidases, peroxiredoxins (Prdx) play integral roles in balancing ROS functions. High levels of Prdx6 are associated with increased metastasis and resistance to chemotherapy, rendering Prdx6 a therapeutic target for treatment of a broad range of cancers. However, Prdx6, has additional activities, in lipid signalling and selenocysteine metabolism, and it remains unclear how Prdx6s thiol peroxidase activity contributes to disease or ageing. Here we have investigated the role/s of Prdx6 in the stress responses and ageing of the nematode worm Caenorhabditis. elegans. Unexpectedly, we have found that C. elegans lacking prdx-6, have an increased resistance to oxidative stress and extended lifespan under some conditions. Moreover, prdx-6 mutant worms are also more resistant to infection with two opportunistic human pathogens; the gram-positive bacteria Staphylococcus aureus and the dimorphic yeast Candida albicans. Our data suggest that increased ROS levels in prdx-6 mutant worms lead to increased cell death in the germ line, and increased expression of the Flavin monooxygenase, FMO-2 in other tissues. FMO-2 has a conserved pro-survival function and is upregulated by the NHR-49(PPAR/HNF4) transcriptional regulator in response to various stresses, including peroxides and S. aureus infection. Here we reveal that fmo-2 expression is also increased as an NHR-49-dependent protective response to C. albicans. Thus, in addition to its anti-ageing role, FMO-2 protects C. elegans against both fungal and bacterial infections. Accordingly, we propose that elevated fmo-2 expression contributes to the increased stress resistance, lifespan and innate immunity of prdx-6 mutant animals. These findings further illustrate the complex roles that ROS/PRDX can play in stress resistance, immunity and ageing. HighlightsO_LIPRDX-6 is expressed in specific interneurons and intestine C_LIO_LILoss of PRDX-6 increases germ cell apoptosis C_LIO_LILoss of PRDX-6 increases C. elegans stress resistance, innate immunity and longevity C_LIO_LILoss of PRDX-6 and infection increase expression of the flavin monooxygenase fmo-2 C_LIO_LIFMO-2 protects against infection with the fungal pathogen Candida albicans C_LI