How a Fungus Warms Up to Its Host

Science Signaling  05 May 2009:
Vol. 2, Issue 69, pp. ec159
DOI: 10.1126/scisignal.269ec159

The potentially deadly fungal pathogen Candida albicans detects its presence in a mammalian host and responds to components of serum and to increases in temperature by initiating a developmental transition from a single-celled budding yeast form to a multicellular filamentous form, the latter being required for maximal virulence. Shapiro et al. report that the response to temperature is mediated by HSP90 (heat shock protein 90), a fascinating molecular chaperone that interacts with many signaling proteins and can allow organisms to enhance genetic and epigenetic variation in response to environmental stress. In C. albicans, Shapiro et al. found that inhibition of Hsp90 was necessary to promote filamentous growth in response to environmental conditions and sufficient to promote filamentous growth in cells that would normally grow in the budding yeast form. The authors suspected that exposure of cells to increased temperature (37°C) might overwhelm specific Hsp90 functions because of increased problems with protein folding in general. Consistent with this idea, filament formation in cells with reduced expression of HSP90 was more sensitive to temperature increases. Similarly, lower doses of pharmacological inhibitor were required to promote filamentous growth at 37°C than at 30°C. Transcriptional regulation by the phosphatase calcineurin, a target of Hsp90, was reduced under conditions that promoted filament formation, consistent with a reduced function of Hsp90 under such conditions. Genetic analysis showed that cells with mutations in the Ras1-PKA pathway [a signaling pathway from the small guanosine triphosphatase Ras1, which activates signaling by the cAMP-dependent protein kinase (PKA) and by mitogen-activated protein kinases] failed to respond to inhibition of Hsp90. Positive and negative genetic epistasis experiments further supported a role of Hsp90 in restraining filamentous differentiation by repressing signaling through the Ras1-PKA pathway. These results, the authors point out, identify Hsp90 as a possible target for antifungal therapies. Indeed, in a mouse model, genetic depletion of Hsp90 completely cleared kidneys of a C. albicans infection.

R. S. Shapiro, P. Uppuluri, A. K. Zaas, C. Collins, H. Senn, J. R. Perfect, J. Heitman, L. E. Cowen, Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling. Curr. Biol. 19, 621–629 (2009). [PubMed]