NHR-14 loss of function couples intestinal iron uptake with innate immunity in C. elegans through PQM-1 signaling

Abstract

Iron is essential for survival of most organisms. All organisms have thus developed mechanisms to sense, acquire and sequester iron. In C. elegans, iron uptake and sequestration are regulated by HIF-1. We previously showed that hif-1 mutants are developmentally delayed when grown under iron limitation. Here we identify nhr-14, encoding a nuclear receptor, in a screen conducted for mutations that rescue the developmental delay of hif-1 mutants under iron limitation. nhr-14 loss upregulates the intestinal metal transporter SMF-3 to increase iron uptake in hif-1 mutants. nhr-14 mutants display increased expression of innate immune genes and DAF-16/FoxO-Class II genes, and enhanced resistance to Pseudomonas aeruginosa. These responses are dependent on the transcription factor PQM-1, which localizes to intestinal cell nuclei in nhr-14 mutants. Our data reveal how C. elegans utilizes nuclear receptors to regulate innate immunity and iron availability, and show iron sequestration as a component of the innate immune response.

Surviving hypothermia by ferritin-mediated iron detoxification

“…While ftn-1 was previously shown to be upregulated upon DAF-2 inactivation, in a DAF-16 dependent manner, ftn-2 is not considered a DAF-16 target 36 . Also, in agreement with their differential regulation in innate immunity, the expression of ftn-1, but not ftn-2, was reported to depend on PQM-1 28 . Confirming our RNA profiling data by RT-qPCR, and consistent with the regulation by both DAF-16 and PQM-1, we observed a DAF-16 and PQM-1 dependent increase in the levels of ftn-1 mRNA in cold-treated ets-4(-) mutants ( Fig.…”

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

“…To identify the potential immune pathways that may play a role in the pathogen resistance to the UNC-30-deficient animals, we performed a gene enrichment analysis using the immune gene subset by employing the Worm Exp tool (https://wormexp.zoologie.uni-kiel.de/wormexp/) (Yang et al, 2016), which integrates all published expression datasets for C. elegans to analyze and generate pathways. We found that pathways required for C. elegans defense against bacterial infections were highly enriched, including the GATA/ELT-2, p38/PMK-1 MAPK, PQM-1, and DAF-2/DAF-16 insulin pathways (Figure 2B and Table S3) (Aballay et al, 2003; Garsin et al, 2003; Head et al, 2017; Huffman et al, 2004; Kerry et al, 2006; Kim et al, 2002; Murphy et al, 2003; Rajan et al, 2019; Shapira et al, 2006; Singh and Aballay, 2006, 2009; Troemel et al, 2006). We also noticed that several of the p38/PMK-1 and FOXO/DAF-16-dependent genes were also controlled by GATA/ELT-2 (Figure S6 and Tables S3), indicating that GATA/ELT-2-dependent genes may play a major role in the enhanced resistance to pathogen phenotype of unc-30(ok613) animals.…”

“…elegans to analyze and generate pathways. We found that pathways required for C. elegans defense against bacterial infections were highly enriched, including the GATA/ELT-2, p38/PMK-1 MAPK, PQM-1, and DAF-2/DAF-16 insulin pathways ( Figure 2B and Table S3) (Aballay et al, 2003;Garsin et al, 2003;Head et al, 2017;Huffman et al, 2004;Kerry et al, 2006;Kim et al, 2002;Murphy et al, 2003;Rajan et al, 2019;Shapira et al, 2006;Aballay, 2006, 2009;Troemel et al, 2006). We also noticed that several of the p38/PMK-1 and FOXO/DAF-16-dependent genes were also controlled by GATA/ELT-2 ( Figure S6 and Tables S3), indicating that GATA/ELT-2-dependent genes may play a major role in the enhanced resistance to pathogen phenotype of unc-30(ok613) animals.…”

Immunometabolism in Caenorhabditis elegans

“…In addition, the C. elegans homolog of the liver X receptor (LXR), NHR-8, which controls cholesterol and bile acid homeostasis, is required for defense against infection with P. aeruginosa [27,28]. Finally, the nuclear hormone receptor NHR-14 links iron availability with the induction of innate immune defenses that provide protection from pathogen infection [29].…”

“…aeruginosa [ 27 , 28 ]. Finally, the nuclear hormone receptor NHR-14 links iron availability with the induction of innate immune defenses that provide protection from pathogen infection [ 29 ].…”