Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi.
Hsp90 is a molecular chaperone for many signal transducers and may influence evolution by releasing previously silent genetic variation in response to environmental change. In fungi separated by approximately 800 million years of evolution, Hsp90 potentiated the evolution of drug resistance in a different way, by enabling new mutations to have immediate phenotypic consequences. Resistance was abrogated by Hsp90 inhibitors and by febrile temperatures, suggesting new therapeutic strategies and a clinical benefit of fever. During selection in a human host, drug resistance that was initially Hsp90-dependent evolved toward independence. Thus, Hsp90 can act in diverse ways to couple environmental contingency to the emergence and fixation of new traits.
Cowen
Leah E
LE
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Lindquist
Susan
S
D017088:AIDS-Related Opportunistic Infections / Q000382:microbiology; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000382:microbiology; D001230:Aspergillus / Q000187:drug effects / Q000235:genetics; D005075:Biological Evolution; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000382:microbiology; D000077336:Caspofungin; D021984:Cyclophilin A / Q000378:metabolism; D025141:Drug Resistance, Fungal; D054714:Echinocandins; D004875:Ergosterol / Q000096:biosynthesis; D015725:Fluconazole / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D055666:Lipopeptides; D009154:Mutation; D010456:Peptides, Cyclic / Q000494:pharmacology; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012641:Selection, Genetic
D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D054714:Echinocandins; C074510:HSP82 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D029701:Saccharomyces cerevisiae Proteins; D015725:Fluconazole; D019703:Calcineurin; D021984:Cyclophilin A; D000077336:Caspofungin; D004875:Ergosterol