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Following phagocytosis, microbes are exposed to an array of antimicrobial weapons that include reactive oxygen species (ROS) and cationic fluxes. This is significant as combinations of oxidative and cationic stresses are much more potent than the corresponding single stresses, triggering the synergistic killing of the fungal pathogen  Candida albicans  by “stress pathway interference.” Previously we demonstrated that combinatorial oxidative plus cationic stress triggers a dramatic increase in intracellular ROS levels compared to oxidative stress alone. Here we show that activation of Cap1, the major regulator of antioxidant gene expression in  C. albicans , is significantly delayed in response to combinatorial stress treatments and to high levels of H 2 O 2 . Cap1 is normally oxidized in response to H 2 O 2 ; this masks the nuclear export sequence, resulting in the rapid nuclear accumulation of Cap1 and the induction of Cap1-dependent genes. Here we demonstrate that following exposure of cells to combinatorial stress or to high levels of H 2 O 2 , Cap1 becomes trapped in a partially oxidized form, Cap1 OX-1 . Notably, Cap1-dependent gene expression is not induced when Cap1 is in this partially oxidized form. However, while Cap1 OX-1  readily accumulates in the nucleus and binds to target genes following high-H 2 O 2  stress, the nuclear accumulation of Cap1 OX-1  following combinatorial H 2 O 2  and NaCl stress is delayed due to a cationic stress-enhanced interaction with the Crm1 nuclear export factor. These findings define novel mechanisms that delay activation of the Cap1 transcription factor, thus preventing the rapid activation of the stress responses vital for the survival of  C. albicans  within the host.

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Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in Candida albicans following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency