Expanded role of the Cu‐sensing transcription factor Mac1p in Candida albicans

Abstract

As part of the innate immune response, the host withholds metal micronutrients such as Cu from invading pathogens, and microbes respond through metal starvation stress responses. With the opportunistic fungal pathogen Candida albicans, the Cu-sensing transcription factor Mac1p governs the cellular response to Cu starvation by controlling Cu import. Mac1p additionally controls reactive oxygen species (ROS) homeostasis by repressing a Cu-containing superoxide dismutase (SOD1) and inducing Mn-containing SOD3 as a non-Cu alternative. We show here that C. albicans Mac1p is essential for virulence in a mouse model for disseminated candidiasis and that the cellular functions of Mac1p extend beyond Cu uptake and ROS homeostasis. Specifically, mac1∆/∆ mutants are profoundly deficient in mitochondrial respiration and Fe accumulation, both Cu-dependent processes. Surprisingly, these deficiencies are not simply the product of impaired Cu uptake; rather mac1∆/∆ mutants appear defective in Cu allocation. The respiratory defect of mac1∆/∆ mutants was greatly improved by a sod1∆/∆ mutation, demonstrating a role for SOD1 repression by Mac1p in preserving respiration. Mac1p downregulates the major Cu consumer SOD1 to spare Cu for respiration that is essential for virulence of this fungal pathogen. The implications for such Cu homeostasis control in other pathogenic fungi are discussed.

Transcription factor–driven alternative localization of Cryptococcus neoformans superoxide dismutase

“…An analogous function may occur in C. neoformans, in which the ubiquitous Sod1 protein is repressed to lower the cellular demand for Cu. Support of this mechanism in pathogenic fungi has recently been published in C. albicans, where a mac1Δ/Δ mutant unable to repress SOD1 expression during Cu deficiency also has a mitochondrial respiratory defect, which is alleviated by introducing the sod1Δ/Δ mutation (67).…”

Copper intoxication in group BStreptococcustriggers transcriptional activation of thecopoperon that contributes to enhanced virulence during acute infection

“…Recently, the Cu-sensing transcription factor Mac1p in Candida was shown to regulate the cells response to Cu starvation by controlling Cu import, and control reactive oxygen species homeostasis by repressing a Cu-containing superoxide dismutase and inducing Mn-containing SOD3 (45). A system for the dual import of Mn and Fe in GBS is encoded by mntH that is regulated by pH (46).…”

“…Mn import and Fe efflux are co-ordinated in order to control the metalation of superoxide dismutase (43), which can use Mn or Fe at its catalytic site in streptococci; noting that Mn uptake can be disrupted by Zn (35). Recently, the Cu-sensing transcription factor Mac1p in Candida was shown to regulate the cells response to Cu starvation by controlling Cu import, and control reactive oxygen species homeostasis by repressing a Cu-containing superoxide dismutase and inducing Mn-containing SOD3 (45). A system for the dual import of Mn and Fe in GBS is encoded by mntH that is regulated by pH (46).…”

Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus

“…In Pseudomonas stutzeri, overlapping regulation of genes that mediate Cu and Zn resistance has recently been reported [34], suggesting that a core set of bacterial genes respond to Cu and Zn, and are co-regulated. A Cu-responsive regulatory system for Cu uptake in Candida was recently shown to encompass an Iron (Fe)-starvation stress response [23]. Collectively, these observations highlight the complexity of bacterial adaptation to metal excess and limitation, and also point to potential cross-talk mechanisms between metal management systems that might be used to support cellular homeostasis and effect bacterial fitness in distinct environments.…”