Candida albicans Hap43 Is a Repressor Induced under Low-Iron Conditions and Is Essential for Iron-Responsive Transcriptional Regulation and Virulence

Abstract

Candida albicans is an opportunistic fungal pathogen that exists as normal flora in healthy human bodies but causes life-threatening infections in immunocompromised patients. In addition to innate and adaptive immunities, hosts also resist microbial infections by developing a mechanism of "natural resistance" that maintains a low level of free iron to restrict the growth of invading pathogens. C. albicans must overcome this irondeprived environment to cause infections. There are three types of iron-responsive transcriptional regulators in fungi; Aft1/Aft2 activators in yeast, GATA-type repressors in many fungi, and HapX/Php4 in Schizosaccharomyces pombe and Aspergillus species. In this study, we characterized the iron-responsive regulator Hap43, which is the C. albicans homolog of HapX/Php4 and is repressed by the GATA-type repressor Sfu1 under iron-sufficient conditions. We provide evidence that Hap43 is essential for the growth of C. albicans under low-iron conditions and for C. albicans virulence in a mouse model of infection. Hap43 was not required for iron acquisition under low-iron conditions. Instead, it was responsible for repression of genes that encode irondependent proteins involved in mitochondrial respiration and iron-sulfur cluster assembly. We also demonstrated that Hap43 executes its function by becoming a transcriptional repressor and accumulating in the nucleus in response to iron deprivation. Finally, we found a connection between Hap43 and the global corepressor Tup1 in low-iron-induced flavinogenesis. Taken together, our data suggest a complex interplay among Hap43, Sfu1, and Tup1 to coordinately regulate iron acquisition, iron utilization, and other ironresponsive metabolic activities.

Interspecies competition triggers virulence and mutability in Candida albicans–Pseudomonas aeruginosa mixed biofilms

“…albicans Hap43p is a repressor that is induced under low-iron conditions and is essential for ironresponsive transcriptional regulation and virulence (Hsu et al, 2011). Consistent with downregulation of C. albicans iron-regulated proteins in mixed biofilms, we found that 19.71% (16) of differentially expressed proteins in mixed biofilms are Hap43p regulated (Supplementary Table S2).…”

Rhb1 Regulates the Expression of Secreted Aspartic Protease 2 through the TOR Signaling Pathway in Candida albicans

“…3C). LexA-Gcn4 and LexA constructs served as positive and negative controls, respectively (31). Compared to wild-type cells, Gat1 and Stp1 showed relatively higher transcriptional activity in cells on the rhb1-deleted background.…”

“…Briefly, the DNA fragment containing the entire GAT1 gene was PCR amplified from the SC5314 genome by the use of primer pair CaGAT1-5= and CaGAT1-3=. The fragment was purified, digested with MluI and PstI, and cloned into the plasmid pCIplexA-F1 (31,64) to generate pCIpLexA-F-Gat1. The plasmid was linearized with StuI, and the lexA-GAT1 fusion fragment was introduced into the RPS1 locus in COP1 and CCR1 strains (31) to generate COP-LexAGat1 and CCR-LexAGat1.…”

Identification and Functional Characterization of Rca1, a Transcription Factor Involved in both Antifungal Susceptibility and Host Response in Candida albicans

“…Hap43 has been demonstrated to interact with Tup1 (30). This overlapping regulation between Rca1 and Hap43 targets further suggests that Tup1 may be involved in the mode of action of Rca1.…”