Multiple HRG-1 paralogs regulate heme homeostasis in <italic>C. elegans</italic>

Abstract

Heme is an essential cofactor for various biological processes although the pathways for cellular heme transport remain poorly understood. We identified HRG-1 as the first bona fide eukaryotic heme importer/transporter using <italic>C. elegans</italic>. The current study seeks to determine how HRG-1 paralogs function in heme transport. We show that CeHRG-6 specifically enhances the heme-dependent growth of the hem1 mutant yeast strain and is therefore a potential heme transporter. HRG-6::GFP is expressed in the intestine, spermathecal valve and uterus. However, worms expressing the HRG-6::GFP transgene reveal a growth defect at low heme concentrations, which is fully rescued with either the addition of heme or RNAi depletion of <italic>hrg-6</italic>, or <italic>hrg-4</italic>. Surprisingly, CeHRG-6 expression is attenuated by RNAi depletion of <italic>hrg-4</italic>. Our results suggest that CeHRG-6 may function in concert with CeHRG-4 to ensure heme uptake in <italic>C. elegans</italic>, and is plausibly regulated by CeHRG-4 under low heme conditions.