Candida albicans Target of Rapamycin in oxidative stress responses

Abstract The goal of this proposal is to examine the role of Candida albicans Tor1 kinase and specifically, its least- conserved domain, N-terminal HEAT repeats, in enabling this fungal pathogen to withstand oxidative stress imposed by the host immune system. We showed that C. albicans cells lacking Tor1 N-terminal HEAT repeats, which are protein-protein interaction domains, are exquisitely hypersensitive to oxidative stress. They also dysregulate dedicated oxidative stress management systems of the fungus, and their metabolic output of intermediates required in redox homeostasis is defective. Tor1 point mutants that we recently engineered, show that these severe defects are not attributable to simple hypo- or hyperactivity of the kinase. Instead, these cells’ oxidative stress management defects appear to relate to functions residing in the N-terminal HEAT repeats. Notably, we found a core enzyme of C. albicans redox homeostasis, that is structurally and functionally completely different than its human counterpart, to be dysregulated in cells lacking Tor1 N-terminal HEAT repeats. We also found that depletion of this enzyme leads to starkly decreased TORC1 signaling even in conditions of ample nutrients and absent stress. We propose to define the interactions between Tor1 and its N-terminal HEAT repeats with dedicated C. albicans oxidative stress management systems.