Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata
Candida glabrata is an emerging human fungal pathogen that is frequently drug tolerant, resulting in difficulties in treatment and a higher mortality in immunocompromised patients. The calcium-activated protein phosphatase calcineurin plays critical roles in controlling drug tolerance, hyphal growth...
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Genetics Society of America
2012
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362297/ |
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pubmed-33622972012-06-12 Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata Chen, Ying-Lien Konieczka, Jay H. Springer, Deborah J. Bowen, Samantha E. Zhang, Jing Silao, Fitz Gerald S. Bungay, Alice Alma C. Bigol, Ursela G. Nicolas, Marilou G. Abraham, Soman N. Thompson, Dawn A. Regev, Aviv Heitman, Joseph Investigations Candida glabrata is an emerging human fungal pathogen that is frequently drug tolerant, resulting in difficulties in treatment and a higher mortality in immunocompromised patients. The calcium-activated protein phosphatase calcineurin plays critical roles in controlling drug tolerance, hyphal growth, and virulence in diverse fungal pathogens via distinct mechanisms involving survival in serum or growth at host temperature (37° and higher). Here, we comprehensively studied the calcineurin signaling cascade in C. glabrata and found novel and uncharacterized functions of calcineurin and its downstream target Crz1 in governing thermotolerance, intracellular architecture, and pathogenesis in murine ocular, urinary tract, and systemic infections. This represents a second independent origin of a role for calcineurin in thermotolerant growth of a major human fungal pathogen, distinct from that which arose independently in Cryptococcus neoformans. Calcineurin also promotes survival of C. glabrata in serum via mechanisms distinct from C. albicans and thereby enables establishment of tissue colonization in a murine systemic infection model. To understand calcineurin signaling in detail, we performed global transcript profiling analysis and identified calcineurin- and Crz1-dependent genes in C. glabrata involved in cell wall biosynthesis, heat shock responses, and calcineurin function. Regulators of calcineurin (RCN) are a novel family of calcineurin modifiers, and two members of this family were identified in C. glabrata: Rcn1 and Rcn2. Our studies demonstrate that Rcn2 expression is controlled by calcineurin and Crz1 to function as a feedback inhibitor of calcineurin in a circuit required for calcium tolerance in C. glabrata. In contrast, the calcineurin regulator Rcn1 activates calcineurin signaling. Interestingly, neither Rcn1 nor Rcn2 is required for virulence in a murine systemic infection model. Taken together, our findings show that calcineurin signaling plays critical roles in thermotolerance and virulence, and that Rcn1 and Rcn2 have opposing functions in controlling calcineurin signaling in C. glabrata. Genetics Society of America 2012-06-01 /pmc/articles/PMC3362297/ /pubmed/22690377 http://dx.doi.org/10.1534/g3.112.002279 Text en Copyright © 2012 Hainer et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Chen, Ying-Lien Konieczka, Jay H. Springer, Deborah J. Bowen, Samantha E. Zhang, Jing Silao, Fitz Gerald S. Bungay, Alice Alma C. Bigol, Ursela G. Nicolas, Marilou G. Abraham, Soman N. Thompson, Dawn A. Regev, Aviv Heitman, Joseph |
| spellingShingle |
Chen, Ying-Lien Konieczka, Jay H. Springer, Deborah J. Bowen, Samantha E. Zhang, Jing Silao, Fitz Gerald S. Bungay, Alice Alma C. Bigol, Ursela G. Nicolas, Marilou G. Abraham, Soman N. Thompson, Dawn A. Regev, Aviv Heitman, Joseph Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata |
| author_facet |
Chen, Ying-Lien Konieczka, Jay H. Springer, Deborah J. Bowen, Samantha E. Zhang, Jing Silao, Fitz Gerald S. Bungay, Alice Alma C. Bigol, Ursela G. Nicolas, Marilou G. Abraham, Soman N. Thompson, Dawn A. Regev, Aviv Heitman, Joseph |
| author_sort |
Chen, Ying-Lien |
| title |
Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata |
| title_short |
Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata |
| title_full |
Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata |
| title_fullStr |
Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata |
| title_full_unstemmed |
Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata |
| title_sort |
convergent evolution of calcineurin pathway roles in thermotolerance and virulence in candida glabrata |
| description |
Candida glabrata is an emerging human fungal pathogen that is frequently drug tolerant, resulting in difficulties in treatment and a higher mortality in immunocompromised patients. The calcium-activated protein phosphatase calcineurin plays critical roles in controlling drug tolerance, hyphal growth, and virulence in diverse fungal pathogens via distinct mechanisms involving survival in serum or growth at host temperature (37° and higher). Here, we comprehensively studied the calcineurin signaling cascade in C. glabrata and found novel and uncharacterized functions of calcineurin and its downstream target Crz1 in governing thermotolerance, intracellular architecture, and pathogenesis in murine ocular, urinary tract, and systemic infections. This represents a second independent origin of a role for calcineurin in thermotolerant growth of a major human fungal pathogen, distinct from that which arose independently in Cryptococcus neoformans. Calcineurin also promotes survival of C. glabrata in serum via mechanisms distinct from C. albicans and thereby enables establishment of tissue colonization in a murine systemic infection model. To understand calcineurin signaling in detail, we performed global transcript profiling analysis and identified calcineurin- and Crz1-dependent genes in C. glabrata involved in cell wall biosynthesis, heat shock responses, and calcineurin function. Regulators of calcineurin (RCN) are a novel family of calcineurin modifiers, and two members of this family were identified in C. glabrata: Rcn1 and Rcn2. Our studies demonstrate that Rcn2 expression is controlled by calcineurin and Crz1 to function as a feedback inhibitor of calcineurin in a circuit required for calcium tolerance in C. glabrata. In contrast, the calcineurin regulator Rcn1 activates calcineurin signaling. Interestingly, neither Rcn1 nor Rcn2 is required for virulence in a murine systemic infection model. Taken together, our findings show that calcineurin signaling plays critical roles in thermotolerance and virulence, and that Rcn1 and Rcn2 have opposing functions in controlling calcineurin signaling in C. glabrata. |
| publisher |
Genetics Society of America |
| publishDate |
2012 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362297/ |
| _version_ |
1611533025084964864 |