Abstract
The Ypd1 phosphorelay protein is a central constituent of fungal two-component signal transduction pathways. Inhibition of Ypd1 in Saccharomyces cerevisiae and Cryptococcus neoformans is lethal due to the sustained activation of the ‘p38-related’ Hog1 stress-activated protein kinase (SAPK). As two-component signalling proteins are not found in animals, Ypd1 is considered to be a prime antifungal target. However, a major fungal pathogen of humans, Candida albicans, can survive the concomitant sustained activation of Hog1 that occurs in cells lacking YPD1. Here we show that the sustained activation of Hog1 upon Ypd1 loss is mediated through the Ssk1 response regulator. Moreover, we present evidence that C. albicans survives SAPK activation in the short-term, following Ypd1 loss, by triggering the induction of protein tyrosine phosphatase-encoding genes which prevent the accumulation of lethal levels of phosphorylated Hog1. In addition, our studies reveal an unpredicted, reversible, mechanism that acts to substantially reduce the levels of phosphorylated Hog1 in ypd1Δ cells following long-term sustained SAPK activation. Indeed, over time, ypd1Δ cells become phenotypically indistinguishable from wild-type cells. Importantly, we also find that drug-induced down-regulation of YPD1 expression actually enhances the virulence of C. albicans in two distinct animal infection models. Investigating the underlying causes of this increased virulence, revealed that drug-mediated repression of YPD1 expression promotes hyphal growth both within murine kidneys, and following phagocytosis, thus increasing the efficacy by which C. albicans kills macrophages. Taken together, these findings challenge the targeting of Ypd1 proteins as a general antifungal strategy and reveal novel cellular adaptation mechanisms to sustained SAPK activation.
Highlights
Candida albicans is the leading cause of systemic fungal infections in humans resulting in over 400,000 deaths each year in immuno-compromised patients [1]
Two-component related proteins, such as the Ypd1 phosphorelay protein, have been heralded as antifungal targets as they are not found in humans and because inactivation of YPD1 in several different fungi causes sustained stress-activated protein kinase (SAPK) activation and cell death
We reveal that this fungus adapts to the sustained activation of the Hog1 SAPK triggered by Ypd1 loss by mounting distinct mechanisms that actively reduce the level of phosphorylated Hog1
Summary
Candida albicans is the leading cause of systemic fungal infections in humans resulting in over 400,000 deaths each year in immuno-compromised patients [1]. Consistent with the vital role of the Hog SAPK in stress survival, C. albicans cells lacking HOG1 display significantly attenuated virulence in systemic, commensal, and phagocyte infection models [8,9,10,11]. All SAPK activation mechanisms reported to date result in the phosphorylation of conserved threonine and tyrosine residues located within the TGY motif of the catalytic domain of the kinase [3]. Such pathways are tightly regulated as the nature of the response is dependent on the extent and period of SAPK activation. Much less is known regarding the regulation and cellular consequences of sustained SAPK activation in C. albicans
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