Crosstalk between iron and flavins in the opportunistic fungal pathogen Candida albicans

As part of the innate immune response, the host withholds metal micronutrients such as iron (Fe) from invading pathogens. To survive such Fe-limitation, the opportunistic fungal pathogen Candida albicans has evolved elaborate responses to Fe-starvation stress. One such adaptation involves the secretion of flavins, yellow isoalloxazine compounds that serve important redox roles in biology. Why the organism secretes flavins during Fe-starvation is not known. Moreover, the exact flavin secreted by the fungus or the effects of Fe-starvation on intracellular flavin pools have not been documented. Major cellular flavins include riboflavin (vitamin B2) and the downstream metabolites and enzyme cofactors FAD and FMN. Of these, our HPLC and mass spectrometry analyses identify riboflavin as the sole flavin secreted by Fe-starved C. albicans. Fe also regulates intracellular pools of flavins. While Fe-replete cells have abundant FMN and FAD with only trace riboflavin, Fe-starvation induces a spike in intracellular riboflavin, whereas FMN and FAD are unaffected. These shifts in riboflavin are dependent on the Fe-sensing transcription factor Sef1. During Fe-starvation, Sef1 induces genes for riboflavin biosynthesis but not for the conversion of riboflavin to FMN and FAD. Sef1 is also needed to activate riboflavin export. We provide evidence for the first time that extracellular riboflavin can enhance fungal uptake of Fe. Specifically, riboflavin increased C. albicans acquisition of Fe from animal serum, presumably through its redox activity on extracellular Fe. Our observed role of riboflavin on Fe uptake may promote C. albicans fitness in the Fe-limiting environment of the host.