# The 1 –Cys peroxiredoxin, PRDX-6, suppresses an NHR-49-dependent pro-survival response, including the Flavin monooxygenase, FMO-2, that protects against fungal and bacterial infection

## TL;DR

The study shows that the protein PRDX-6 in worms influences lifespan, immunity, and stress resistance by regulating other genes like FMO-2 and NHR-49.

## Contribution

The paper reveals a novel protective role of NHR-49-dependent FMO-2 in prdx-6 mutants against infection and stress.

## Key findings

- Loss of PRDX-6 increases lifespan and resistance to arsenite and pathogens in C. elegans.
- PRDX-6 loss leads to increased NHR-49 activity and FMO-2 expression, which protects against infection.
- NHR-49-driven MUFA synthesis is essential for embryonic development in prdx-6 mutants.

## 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 signaling and selenocysteine metabolism, and it remains unclear how Prdx6's thiol peroxidase activity contributes to disease. Here we have investigated the role/s of Prdx6 in the nematode worm Caenorhabditis elegans. Consistent with a ROS-protective role for PRDX-6, prdx-6 mutant C. elegans exhibit elevated levels of lipid oxidation, more apoptotic corpses in their germline and are more susceptible to the toxicity of diethyl maleate. However, unexpectedly, prdx-6 mutant C. elegans are more resistant to other forms of oxidative stress, long-lived and resistant to infection with two opportunistic human pathogens; the gram-positive bacteria Staphylococcus aureus and the dimorphic yeast Candida albicans. Our data suggest these phenotypes are associated with increased activity of the NHR-49(PPARα/HNF4) transcriptional regulator and intestinal expression of the Flavin monooxygenase, FMO-2. FMO-2 has a conserved, pro-survival function and is up-regulated 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. Consistent with increased NHR-49 activity, prdx-6 mutant animals also contain increased levels of mono-unsaturated fatty acids. Accordingly, we propose that elevated expression of fmo-2 and other NHR-49 up-regulated genes contribute to the increased arsenite resistance and innate immunity of prdx-6 mutant animals. These findings further illustrate the complex roles that ROS, PRDX and lipid oxidation can play in oxidative stress resistance, immunity and ageing.

Image 1

•PRDX-6 protects against lipid hydroperoxides, germ cell apoptosis and DEM toxicity.•Loss of PRDX-6 increases lifespan, arsenite resistance and innate immunity of C. elegans.•Loss of PRDX-6, bacterial and fungal infection all increase NHR-49-dependent expression of the flavin monooxygenase fmo-2.•FMO-2 protects against infection and is important for the effects of prdx-6 on arsenite resistance and ageing.•NHR-49-driven increased MUFA synthesis is required for the embryonic development of prdx-6 mutant C.
elegans.

PRDX-6 protects against lipid hydroperoxides, germ cell apoptosis and DEM toxicity.

Loss of PRDX-6 increases lifespan, arsenite resistance and innate immunity of C. elegans.

Loss of PRDX-6, bacterial and fungal infection all increase NHR-49-dependent expression of the flavin monooxygenase fmo-2.

FMO-2 protects against infection and is important for the effects of prdx-6 on arsenite resistance and ageing.

NHR-49-driven increased MUFA synthesis is required for the embryonic development of prdx-6 mutant C.
elegans.