The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation

Jinglin L Xie, Longguang Qin, Zhengqiang Miao, Ben T Grys, Jacinto De La Cruz Diaz, Kenneth Ting, Jonathan R Krieger, Jiefei Tong, Kaeling Tan, Michelle D Leach, Troy Ketela, Michael F Moran, Damian J Krysan, Charles Boone, Brenda J Andrews, Anna Selmecki, Koon Ho Wong, Nicole Robbins, Leah E Cowen

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Abstract

The capacity to coordinate environmental sensing with initiation of cellular responses underpins microbial survival and is crucial for virulence and stress responses in microbial pathogens. Here we define circuitry that enables the fungal pathogen Candida albicans to couple cell cycle dynamics with responses to cell wall stress induced by echinocandins, a front-line class of antifungal drugs. We discover that the C. albicans transcription factor Cas5 is crucial for proper cell cycle dynamics and responses to echinocandins, which inhibit β-1,3-glucan synthesis. Cas5 has distinct transcriptional targets under basal and stress conditions, is activated by the phosphatase Glc7, and can regulate the expression of target genes in concert with the transcriptional regulators Swi4 and Swi6. Thus, we illuminate a mechanism of transcriptional control that couples cell wall integrity with cell cycle regulation, and uncover circuitry governing antifungal drug resistance.

Original languageEnglish
Article number499
Pages (from-to)1-18
Number of pages18
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 11 Sep 2017

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Candida
Candida albicans
Drug Resistance
Echinocandins
Cell Cycle
drugs
Transcription Factors
Cells
Cell Wall
cycles
Fungal Drug Resistance
Pharmaceutical Preparations
Glucans
Phosphoric Monoester Hydrolases
Virulence
virulence
phosphatases
pathogens
regulators
Gene Expression

Keywords

  • Journal Article

Cite this

Xie, J. L., Qin, L., Miao, Z., Grys, B. T., Diaz, J. D. L. C., Ting, K., ... Cowen, L. E. (2017). The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation. Nature Communications, 8, 1-18. [499]. https://doi.org/10.1038/s41467-017-00547-y

The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation. / Xie, Jinglin L; Qin, Longguang; Miao, Zhengqiang; Grys, Ben T; Diaz, Jacinto De La Cruz; Ting, Kenneth; Krieger, Jonathan R; Tong, Jiefei; Tan, Kaeling; Leach, Michelle D; Ketela, Troy; Moran, Michael F; Krysan, Damian J; Boone, Charles; Andrews, Brenda J; Selmecki, Anna; Ho Wong, Koon; Robbins, Nicole; Cowen, Leah E.

In: Nature Communications, Vol. 8, 499, 11.09.2017, p. 1-18.

Research output: Contribution to journalArticle

Xie, JL, Qin, L, Miao, Z, Grys, BT, Diaz, JDLC, Ting, K, Krieger, JR, Tong, J, Tan, K, Leach, MD, Ketela, T, Moran, MF, Krysan, DJ, Boone, C, Andrews, BJ, Selmecki, A, Ho Wong, K, Robbins, N & Cowen, LE 2017, 'The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation', Nature Communications, vol. 8, 499, pp. 1-18. https://doi.org/10.1038/s41467-017-00547-y
Xie, Jinglin L ; Qin, Longguang ; Miao, Zhengqiang ; Grys, Ben T ; Diaz, Jacinto De La Cruz ; Ting, Kenneth ; Krieger, Jonathan R ; Tong, Jiefei ; Tan, Kaeling ; Leach, Michelle D ; Ketela, Troy ; Moran, Michael F ; Krysan, Damian J ; Boone, Charles ; Andrews, Brenda J ; Selmecki, Anna ; Ho Wong, Koon ; Robbins, Nicole ; Cowen, Leah E. / The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation. In: Nature Communications. 2017 ; Vol. 8. pp. 1-18.
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abstract = "The capacity to coordinate environmental sensing with initiation of cellular responses underpins microbial survival and is crucial for virulence and stress responses in microbial pathogens. Here we define circuitry that enables the fungal pathogen Candida albicans to couple cell cycle dynamics with responses to cell wall stress induced by echinocandins, a front-line class of antifungal drugs. We discover that the C. albicans transcription factor Cas5 is crucial for proper cell cycle dynamics and responses to echinocandins, which inhibit β-1,3-glucan synthesis. Cas5 has distinct transcriptional targets under basal and stress conditions, is activated by the phosphatase Glc7, and can regulate the expression of target genes in concert with the transcriptional regulators Swi4 and Swi6. Thus, we illuminate a mechanism of transcriptional control that couples cell wall integrity with cell cycle regulation, and uncover circuitry governing antifungal drug resistance.",
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AU - Krieger, Jonathan R

AU - Tong, Jiefei

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N1 - We thank Cowen lab members for helpful discussions. We also thank David Rogers (University of Tennessee) for sharing microarray analysis of the CAS5 homozygous mutant, and Li Ang (University of Macau) for assistance in optimizing the ChIP-Seq experiments. J.L.X. is supported by a Canadian Institutes of Health Research Doctoral award and M.D.L. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust 096072). B.T.G. holds an Ontario Graduate Scholarship. C.B. and B.J.A. are supported by the Canadian Institutes of Health Research Foundation Grants (FDN-143264 and -143265). D.J.K. is supported by a National Institute of Allergy and Infectious Diseases grant (1R01AI098450) and J.D.L.C.D. is supported by the University of Rochester School of Dentistry and Medicine PREP program (R25 GM064133). A.S. is supported by the Creighton University and the Nebraska Department of Health and Human Services (LB506-2017-55). K.H.W. is supported by the Science and Technology Development Fund of Macau S.A.R. (FDCT; 085/2014/A2). L.E.C. is supported by the Canadian Institutes of Health Research Operating Grants (MOP-86452 and MOP-119520), the Natural Sciences and Engineering Council (NSERC) of Canada Discovery Grants (06261 and 462167), and an NSERC E.W.R. Steacie Memorial Fellowship (477598).

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AB - The capacity to coordinate environmental sensing with initiation of cellular responses underpins microbial survival and is crucial for virulence and stress responses in microbial pathogens. Here we define circuitry that enables the fungal pathogen Candida albicans to couple cell cycle dynamics with responses to cell wall stress induced by echinocandins, a front-line class of antifungal drugs. We discover that the C. albicans transcription factor Cas5 is crucial for proper cell cycle dynamics and responses to echinocandins, which inhibit β-1,3-glucan synthesis. Cas5 has distinct transcriptional targets under basal and stress conditions, is activated by the phosphatase Glc7, and can regulate the expression of target genes in concert with the transcriptional regulators Swi4 and Swi6. Thus, we illuminate a mechanism of transcriptional control that couples cell wall integrity with cell cycle regulation, and uncover circuitry governing antifungal drug resistance.

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