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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Genetics Society of America, The
2013
|
| Online Access: | http://hdl.handle.net/1721.1/80304 https://orcid.org/0000-0001-8567-2049 |
| _version_ | 1826196651516100608 |
|---|---|
| author | Regev, Aviv Chen, Ying-Lien Konieczka, Jay 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. Heitman, Joseph |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Regev, Aviv Chen, Ying-Lien Konieczka, Jay 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. Heitman, Joseph |
| author_sort | Regev, Aviv |
| collection | MIT |
| 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. |
| first_indexed | 2024-09-23T10:32:32Z |
| format | Article |
| id | mit-1721.1/80304 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:32:32Z |
| publishDate | 2013 |
| publisher | Genetics Society of America, The |
| record_format | dspace |
| spelling | mit-1721.1/803042022-09-27T09:54:11Z Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata Regev, Aviv Chen, Ying-Lien Konieczka, Jay 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. Heitman, Joseph Massachusetts Institute of Technology. Department of Biology Regev, Aviv Regev, Aviv 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. Duke University Center for AIDS Research 2013-08-27T16:37:11Z 2013-08-27T16:37:11Z 2012-06 2012-02 Article http://purl.org/eprint/type/JournalArticle 2160-1836 http://hdl.handle.net/1721.1/80304 Chen, Y.-L., J. H. Konieczka, D. J. Springer, S. E. Bowen, J. Zhang, F. G. S. Silao, A. A. C. Bungay, et al. “Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata.” G3: Genes|Genomes|Genetics 2, no. 6 (June 1, 2012): 675-691. https://orcid.org/0000-0001-8567-2049 en_US http://dx.doi.org/10.1534/g3.112.002279 G3: Genes-Genomes-Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/3.0/ application/pdf Genetics Society of America, The Regev via Courtney Crummett |
| spellingShingle | Regev, Aviv Chen, Ying-Lien Konieczka, Jay 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. Heitman, Joseph Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata |
| title | 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_short | 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 |
| url | http://hdl.handle.net/1721.1/80304 https://orcid.org/0000-0001-8567-2049 |
| work_keys_str_mv | AT regevaviv convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT chenyinglien convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT konieczkajay convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT springerdeborahj convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT bowensamanthae convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT zhangjing convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT silaofitzgeralds convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT bungayalicealmac convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT bigolurselag convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT nicolasmariloug convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT abrahamsomann convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT thompsondawna convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata AT heitmanjoseph convergentevolutionofcalcineurinpathwayrolesinthermotoleranceandvirulenceincandidaglabrata |