PKC signaling regulates drug resistance of the fungal pathogen candida albicans via circuitry comprised of mkc1, calcineurin, and hsp90

Shantelle L. Lafayette, Cathy Collins, Aimee K. Zaas, Wiley A. Schell, Marisol Betancourt-Quiroz, Leslie Gunatilaka, John R. Perfect, Leah E. Cowen

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to lifethreatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC), which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK) cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which Hsp90 regulates drug resistance, and that targeting stress response signaling provides a promising strategy for treating life-threatening fungal infections.

Original languageEnglish (US)
Article numbere1001069
Pages (from-to)79-80
Number of pages2
JournalPLoS Pathogens
Volume6
Issue number8
DOIs
StatePublished - Aug 2010

Fingerprint

Fungal Drug Resistance
Calcineurin
Candida albicans
Azoles
Protein Kinase C
Drug Resistance
Ergosterol
Mycoses
Mitogen-Activated Protein Kinases
Cell Wall
Saccharomyces cerevisiae
Morpholines
Allylamine
Cell Membrane
Pharmaceutical Preparations
Molecular Chaperones
Sterols
Drug Delivery Systems
Morphogenesis
Virulence

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

PKC signaling regulates drug resistance of the fungal pathogen candida albicans via circuitry comprised of mkc1, calcineurin, and hsp90. / Lafayette, Shantelle L.; Collins, Cathy; Zaas, Aimee K.; Schell, Wiley A.; Betancourt-Quiroz, Marisol; Gunatilaka, Leslie; Perfect, John R.; Cowen, Leah E.

In: PLoS Pathogens, Vol. 6, No. 8, e1001069, 08.2010, p. 79-80.

Research output: Contribution to journalArticle

Lafayette, SL, Collins, C, Zaas, AK, Schell, WA, Betancourt-Quiroz, M, Gunatilaka, L, Perfect, JR & Cowen, LE 2010, 'PKC signaling regulates drug resistance of the fungal pathogen candida albicans via circuitry comprised of mkc1, calcineurin, and hsp90', PLoS Pathogens, vol. 6, no. 8, e1001069, pp. 79-80. https://doi.org/10.1371/journal.ppat.1001069
Lafayette, Shantelle L. ; Collins, Cathy ; Zaas, Aimee K. ; Schell, Wiley A. ; Betancourt-Quiroz, Marisol ; Gunatilaka, Leslie ; Perfect, John R. ; Cowen, Leah E. / PKC signaling regulates drug resistance of the fungal pathogen candida albicans via circuitry comprised of mkc1, calcineurin, and hsp90. In: PLoS Pathogens. 2010 ; Vol. 6, No. 8. pp. 79-80.
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