Homeostatic control of an iron repressor in a GI tract resident

Abstract

AbstractThe transition metal iron plays a crucial role in living cells. However, high level of iron is potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungusCandida albicansfor colonization in the iron-rich gastrointestinal (GI) tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications (PTMs) and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 lead to de-repression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress-adaptation ofC. albicansto gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism.ImportanceIron homeostasis is critical for creatures.Candida albicansis one of the major commensals in the GI tract where is iron-replete environment. Transcriptional factor Hap43 was believed to repress iron utilizations genes in iron-depleted conditions for decades. However, the mystery in iron-replete conditions of Hap43 has never been uncovered. We discovered that reduced levels of Hap43 via phosphorylation-dependent nuclear export, followed by proteosome-mediated protein degradation, leads to de-repression of downstream antioxidant genes and promote its colonization in GI tract. We propose thatC. albicanshas a strict detoxification process to ensure its survival, which has important implications for understanding how the fungi survives in the mammalian host.