the hsp90 co-chaperone sgt1 governs candida albicans morphogenesis and drug resistance的一半co-chaperone sgt1控制白色念珠菌形态发生和耐药.pdfVIP

The Hsp90 Co-Chaperone Sgt1 Governs Candida albicans Morphogenesis and Drug Resistance 1 2,3 2 2,3 1 Rebecca S. Shapiro , Aimee K. Zaas , Marisol Betancourt-Quiroz , John R. Perfect , Leah E. Cowen * 1 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada, 2 Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America, 3 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America Abstract The molecular chaperone Hsp90 orchestrates regulatory circuitry governing fungal morphogenesis, biofilm development, drug resistance, and virulence. Hsp90 functions in concert with co-chaperones to regulate stability and activation of client proteins, many of which are signal transducers. Here, we characterize the first Hsp90 co-chaperone in the leading human fungal pathogen, Candida albicans. We demonstrate that Sgt1 physically interacts with Hsp90, and that it governs C. albicans morphogenesis and drug resistance. Genetic depletion of Sgt1 phenocopies depletion of Hsp90, inducing yeast to filament morphogenesis and invasive growth. Sgt1 governs these traits by bridging two morphogenetic regulators: Hsp90 and the adenylyl cyclase of the cAMP-PKA signaling cascade, Cyr1. Sgt1 physically interacts with Cyr1, and depletion of either Sgt1 or Hsp90 activates cAMP-PKA signaling, revealing the elusive link between Hsp90 and the PKA signaling cascade. Sgt1 also mediates tolerance and resistance to the two most widely deployed classes of antifungal drugs, azoles and echinocandins. Depletion of Sgt1 abrogates basal