Mds3 Regulates Morphogenesis in Candida albicans through the TOR Pathway

Abstract

The success of Candida albicans as a major human fungal pathogen is dependent on its ability to colonize and survive as a commensal on diverse mucosal surfaces. One trait required for survival and virulence in the host is the morphogenetic yeast-to-hypha transition. Mds3 was identified as a regulator of pH-dependent morphogenesis that functions in parallel with the classic Rim101 pH-sensing pathway. Microarray analyses revealed that mds3Δ/Δ cells had an expression profile indicative of a hyperactive TOR pathway, including the preferential expression of genes encoding ribosomal proteins and a decreased expression of genes involved in nitrogen source utilization. The transcriptional and morphological defects of the mds3Δ/Δ mutant were rescued by rapamycin, an inhibitor of TOR, and this rescue was lost in strains carrying the rapamycin-resistant TOR1-1 allele or an rbp1Δ/Δ deletion. Rapamycin also rescued the transcriptional and morphological defects associated with the loss of Sit4, a TOR pathway effector, but not the loss of Rim101 or Ras1. The sit4Δ/Δ and mds3Δ/Δ mutants had additional phenotypic similarities, suggesting that Sit4 and Mds3 function similarly in the TOR pathway. Finally, we found that Mds3 and Sit4 coimmunoprecipitate. Thus, Mds3 is a new member of the TOR pathway that contributes to morphogenesis in C. albicans as a regulator of this key morphogenetic pathway.

Supplemental material for this article may be found at http://mcb.asm.org/.

This work was supported by the Investigators in Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund to D.A.D. and by the NIH National Institute of Allergy and Infectious Diseases award R01-AI064054 to D.A.D.

We thank Eric Bensen and Zhen Jin Tu for assistance with microarray analysis and Gabriela Vazquez for statistical analysis. We also are indebted to Ed Winter, Doreen Harcus, Joseph Heitman, and Malcolm Whiteway for strains. Finally, we are grateful to Judith Berman, Kirsten Nielsen, Timothy Brickman, Do-Hyung Kim, Thomas Neufeld, and the members of the Davis laboratory for numerous helpful discussions and the critical reading of the manuscript.