The Caenorhabditis elegans Oxidative Stress Response Requires the NHR-49 Transcription Factor

Abstract

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegans BRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of nhr-49 promote gst-4 expression. We also demonstrate that nhr-49 and its cofactor mdt-15 are required to express phase II detoxification enzymes upon exposure to chemicals that induce oxidative stress. Furthermore, we show that NHR-49 and MDT-15 enhance expression of skn-1a/c. These findings identify a novel role for NHR-49 in ROS detoxification by regulating expression of SKN-1C and phase II detoxification genes.

Nuclear hormone receptor NHR-49 shapes immuno-metabolic response ofCaenorhabditis elegans to Enterococcus faecalisinfection

“…It has been reported that NHR-49 activity positively regulates expression of detoxification genes such as glutathione-S-transferase (gst-4). While we were writing the manuscript another study indicated that flavin mono-oxygenase (fmo-2) upregulation during oxidative stress was dependent on NHR-49 (Qi et al, 2017;Goh et al, 2018;Hu et al, 2018). Our study shows that NHR-49 regulates detoxification enzymes in the context of infection as well.…”

NHR-49 Transcription Factor Regulates Immunometabolic Response and Survival of Caenorhabditis elegans during Enterococcus faecalis Infection

“…It is important to note that ROS has also been linked to the death of the nematodes during E. faecalis infection ( 34 ). Additionally, NHR-49 is also activated during organic peroxide treatment and causes induction of cytoprotective factors, including FMO-2 ( 35 , 36 ).…”

“…It is important to note that ROS has also been linked to the death of worms during E. faecalis infection(34). Additionally, NHR-49 is also activated during organic peroxide treatment and causes induction of cytoprotective factors including FMO-2(35,36).LD homeostasis entails a balance between lipid breakdown and synthesis. The homeostasis is maintained by conserved molecular players such as SREBP (SBP-1), PPARα (NHR-49), TOR, AMPK and hexosamine.…”

NHR-49/PPAR-α and HLH-30/TFEB promoteC. eleganshost defense via a flavin-containing monooxygenase

“…NHR-49/PPAR-α is better known in C. elegans as a transcription factor that is important for the response to starvation (Van Gilst et al, 2005). However, recently NHR-49/PPAR-α was shown to mediate the defense response to exogenous oxidative stress (Goh et al, 2018;Hu et al, 2018). Thus, NHR-49/PPAR-α participates in host defense against biotic and abiotic stressors, and should be considered a key player in the organismal stress response alongside SKN-1/NRF, DAF-16/FOXO3, and HLH-30/TFEB (Blackwell et al, 2015;Lin et al, 2018;Tissenbaum, 2018).…”

“…Previous studies identified NHR-49, a nuclear receptor homologous to human PPAR-α and HNF4-α, as essential for fmo-2/FMO5 induction during exogenous oxidative stress (Goh et al, 2018;Hu et al, 2018). To examine the role of NHR-49/PPAR-α during infection, we checked fmo-2/FMO5 expression in nhr-49/PPARA null mutants (Liu et al, 1999;Van Gilst et al, 2005).…”