Candida albicans FRE8 encodes a member of the NADPH oxidase family that produces a burst of ROS during fungal morphogenesis

Abstract

Until recently, NADPH oxidase (NOX) enzymes were thought to be a property of multicellularity, where the reactive oxygen species (ROS) produced by NOX acts in signaling processes or in attacking invading microbes through oxidative damage. We demonstrate here that the unicellular yeast and opportunistic fungal pathogen Candida albicans is capable of a ROS burst using a member of the NOX enzyme family, which we identify as Fre8. C. albicans can exist in either a unicellular yeast-like budding form or as filamentous multicellular hyphae or pseudohyphae, and the ROS burst of Fre8 begins as cells transition to the hyphal state. Fre8 is induced during hyphal morphogenesis and specifically produces ROS at the growing tip of the polarized cell. The superoxide dismutase Sod5 is co-induced with Fre8 and our findings are consistent with a model in which extracellular Sod5 acts as partner for Fre8, converting Fre8-derived superoxide to the diffusible H2O2 molecule. Mutants of fre8Δ/Δ exhibit a morphogenesis defect in vitro and are specifically impaired in development or maintenance of elongated hyphae, a defect that is rescued by exogenous sources of H2O2. A fre8Δ/Δ deficiency in hyphal development was similarly observed in vivo during C. albicans invasion of the kidney in a mouse model for disseminated candidiasis. Moreover C. albicans fre8Δ/Δ mutants showed defects in a rat catheter model for biofilms. Together these studies demonstrate that like multicellular organisms, C. albicans expresses NOX to produce ROS and this ROS helps drive fungal morphogenesis in the animal host.

Metabolism‐induced oxidative stress and DNA damage selectively trigger genome instability in polyploid fungal cells

“…Notably, tetraploid cells grown on PRE-SPO medium exhibited the strongest signal, with 2.0-fold higher fluorescence levels than diploid cells on this medium ( Fig 4B). Previous work showed that C. albicans also produces ROS during hyphal morphogenesis (Rossi et al, 2017). Consistent with this finding, cells grown on YPD medium at 37°C, a growth condition which induces filamentation, stained positively with CellROX Green ( Fig EV3A).…”

“…Previous work showed that C. albicans also produces ROS during hyphal morphogenesis (Rossi et al , ). Consistent with this finding, cells grown on YPD medium at 37°C, a growth condition which induces filamentation, stained positively with CellROX Green (Fig EV3A).…”

Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains

“…However, we recently found that Cu-only SOD5 from unicellular C. albicans can act in signaling involving ROS and a fungal NOX enzyme known as FRE8 (78). C. albicans FRE8 and SOD5 together generate H 2 O 2 that can help drive morphogenesis of the fungus into an invasive filamentous state (78).…”

Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens

“…Recent studies have shown that C. albicans produces a burst of extracellular O 2 ·− by a fungal NOX enzyme (FRE8) during morphogenesis and that this O 2 ·− serves as a substrate for extracellular Cu-only SOD5. The diffusible H 2 O 2 product generated by SOD5 then acts as a signal to modulate morphogenesis through a mechanism that is currently not known 146 . In fact, SOD5 is specifically induced during the fungal oxidative burst, indicating that SOD5 may have evolved to deal with fungal-derived ROS 138 .…”