NHR-14 loss of function couples intestinal iron uptake with innate immunity in <i>C. elegans</i> 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 <i>C. elegan</i>s, iron uptake and sequestration are regulated by HIF-1. We previously showed that <i>hif-1</i> mutants are developmentally delayed when grown under iron limitation. Here we identify <i>nhr-14</i>, encoding a nuclear receptor, in a screen conducted for mutations that rescue the developmental delay of <i>hif-1</i> mutants under iron limitation. <i>nhr-14</i> loss upregulates the intestinal metal transporter SMF-3 to increase iron uptake in <i>hif-1</i> mutants. <i>nhr-14</i> mutants display increased expression of innate immune genes and DAF-16/FoxO-Class II genes, and enhanced resistance to <i>Pseudomonas aeruginosa</i>. These responses are dependent on the transcription factor PQM-1, which localizes to intestinal cell nuclei in <i>nhr-14</i> mutants. Our data reveal how <i>C. elegans</i> utilizes nuclear receptors to regulate innate immunity and iron availability, and show iron sequestration as a component of the innate immune response.