Iron is essential for survival of most organisms, but is toxic in excess. 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 loss of function mutants are developmentally delayed when grown under iron limitation. Here we identify
nhr-14, encoding a nuclear receptor homologous to vertebrate HNF4, in a genetic screen conducted for mutations that rescue the developmental delay of
hif-1 mutants under iron limitation. NHR-14 is highly expressed in intestinal cell nuclei and in head cells. We found NHR-14 subcellular localization and expression are not regulated by iron. Loss of
nhr-14 leads to the upregulation of the intestinal metal transporter SMF-3 that increases iron uptake in
hif-1 mutants, rescuing the low iron-dependent developmental delay. Loss of
nhr-14 also promotes the nuclear localization of the zinc-finger transcription factor PQM-1, which activates
smf-3 through the interaction with GATA-like DAF-16-associated elements (DAEs) in the
smf-3 promoter. In addition to
smf-3, RNA-seq analysis revealed upregulation of innate immune response genes as well as DAF-16/FoxO-suppressed Class 2 genes, which are known to be regulated by PQM-1. Consistent with the upregulation of innate immune response genes,
nhr-14 mutants showed enhanced resistance to the human pathogen Pseudomonas aeruginosa that depends in part on the upregulation of
smf-3 dependent iron uptake as well as the upregulation of innate immune response genes. P. aeruginosa reduces expression of
nhr-14 in wild-type N2 worms, which is associated with PQM-1 nuclear localization. We propose that increased iron uptake by SMF-3 is a strategy to limit the acquisition of intestinal iron by pathogens, and may serve as a critical component of the host innate immune response. In summary, the identification of NHR-14 adds a new layer of regulation that links iron metabolism with the innate immune response and provides new insights by which C. elegans responds to pathogen infections.