Mapping the Hsp90 Genetic Interaction Network in Candida albicans Reveals Environmental Contingency and Rewired Circuitry

摘要

The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, and evolution. Hsp90 interacts with ～10% of the proteome in the model yeast Saccharomyces cerevisiae , while only two interactions have been identified in Candida albicans , the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time. Author Summary Hsp90 is an essential and conserved molecular chaperone in eukaryotes that assists with folding diverse proteins, especially regulators of cellular signaling. By activating signaling in response to environmental cues, Hsp90 has a profound impact on myriad aspects of biology. In fungi, Hsp90 influences development, drug resistance, and evolution. In the model yeast Saccharomyces cerevisiae , Hsp90 interacts with ～10% of proteins. In the leading human fungal pathogen, Candida albicans , only two interactions have been identified. We conducted a chemical genetic screen to elucidate the C. albicans Hsp90 interaction network under diverse stress conditions. The majority of the 226 genetic interactors are important for growth under specific conditions, suggesting that they act downstream of Hsp90 and that the network is environmentally contingent. For example, the kinase Hog1 depends upon Hsp90 for activation. Only a few interactors are important for growth in many conditions, suggesting that they act upstream of Hsp90. For example, the protein kinase CK2 regulates function of the Hsp90 chaperone machine and the transcription factor Ahr1 governs HSP90 expression. Thus, we identify novel effectors upstream and downstream of Hsp90, and establish the first chaperone network of a fungal pathogen, with evidence for environmental contingency and network rewiring over evolutionary time.