Abstract
The evolutionarily conserved heat shock transcription factor Hsf1 plays a central role in thermal adaptation in the major fungal pathogen of humans, Candida albicans. Hsf1 becomes hyperphosphorylated in response to heat shock and activates the transcription of genes with heat shock elements (HSEs) in their promoters, these genes contributing to thermal adaptation. However, the relevance of Hsf1 activation to C. albicans virulence is not clear as this pathogen is thought to be obligately associated with warm blooded animals, and this issue has not been tested because HSF1 is essential for viability in C. albicans. In this study, we demonstrate that the HSE regulon is active in C. albicans cells infecting the kidney. We also show the CE2 region of Hsf1 is required for activation and that the phosphorylation of specific residues in this domain contributes to Hsf1 activation. C. albicans HSF1 mutants that lack this CE2 region are viable. However, they are unable to activate HSE-containing genes in response to heat shock, and they are thermosensitive. Using this HSF1 CE2 deletion mutant we demonstrate that Hsf1 activation, and hence thermal adaptation, contributes significantly to the virulence of C. albicans.
Highlights
The major fungal pathogen of humans, Candida albicans, exists in many healthy individuals as a relatively harmless commensal organism in the microflora of the oral cavity and theThis document was posted here by permission of the publisher
Cells expressing the phosphomimetic SDM-E allele displayed a significant increase in heat resistance compared to the SDM-WT control, whereas cells expressing the non-phosphorylatable SDM-A allele showed a small but statistically significant decrease in thermotolerance. These results suggest that, additional Hsf1 residues appear to be phosphorylated in response to heat shock, the observed phosphorylation at S571, T575, S577 and T578 contributes to thermotolerance in C. albicans
The CE2 domain harbours four amino acid residues at which phosphorylation has been detected in C. albicans cells: S571, T575, S577 and T578 (Beltrao et al, 2009; Kaffarnik and Peck, unpublished)
Summary
This document was posted here by permission of the publisher. The U.S National Library of Medicine is responsible for all links within the document and for incorporating any publisher-supplied amendments or retractions issued subsequently. C. albicans is a frequent cause of mucosal infections such as oral thrush and vaginitis (Ruhnke, 2002). These infections generally arise when host immune defenses are weakened or the local microflora is disturbed. In patients with severely compromised immune defenses, e.g. in chemotherapy or transplant patients, C. albicans can establish potentially fatal systemic infections of the bloodstream and of major organs such as the kidney, liver and brain (Filler and Kullberg, 2002; Kullberg and Filler, 2002)
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