Abstract
Candida albicans colonises numerous niches within humans and thus its success as a pathogen is dependent on its ability to adapt to diverse growth environments within the host. Two component signal transduction is a common mechanism by which bacteria respond to environmental stimuli and, although less common, two component-related pathways have also been characterised in fungi. Here we report the identification and characterisation of a novel two component response regulator protein in C. albicans which we have named CRR1 (Candida Response Regulator 1). Crr1 contains a receiver domain characteristic of response regulator proteins, including the conserved aspartate that receives phosphate from an upstream histidine kinase. Significantly, orthologues of CRR1 are present only in fungi belonging to the Candida CTG clade. Deletion of the C. albicans CRR1 gene, or mutation of the predicted phospho-aspartate, causes increased sensitivity of cells to the oxidising agent hydrogen peroxide. Crr1 is present in both the cytoplasm and nucleus, and this localisation is unaffected by oxidative stress or mutation of the predicted phospho-aspartate. Furthermore, unlike the Ssk1 response regulator, Crr1 is not required for the hydrogen peroxide-induced activation of the Hog1 stress-activated protein kinase pathway, or for the virulence of C. albicans in a mouse model of systemic disease. Taken together, our data suggest that Crr1, a novel response regulator restricted to the Candida CTG clade, regulates the response of C. albicans cells to hydrogen peroxide in a Hog1-independent manner that requires the function of the conserved phospho-aspartate.
Highlights
Two component signal transduction is a primary mechanism utilised by bacteria to respond to environmental stimuli
We demonstrate that Crr1 is involved in the response of C. albicans to hydrogen peroxide stress, but not to other oxidising agents or a range of other stress conditions
Our data suggests that the novel response regulator protein Crr1 functions in a hitherto unidentified two component signal transduction pathway to regulate the response of C. albicans to hydrogen peroxide
Summary
Two component signal transduction is a primary mechanism utilised by bacteria to respond to environmental stimuli These signalling modules are comprised of a sensor histidine kinase and a response regulator protein containing a receiver domain [1]. In contrast to the bacterial systems, a more complex multi-step phosphorelay involving three components appears to predominate in eukaryotic systems Such eukaryotic pathways typically consist of a hybrid sensor histidine kinase, containing both kinase and receiver domains, an intermediary phosphorelay protein and a response regulator protein containing a receiver domain. In these cases phosphate is transferred from a histidine residue in the kinase domain to an aspartate residue located in the receiver domain of the histidine kinase. This phosphate is transferred to a histidine residue in the phosphorelay protein which completes transfer to an aspartate residue in the receiver domain of the response regulator
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