Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata

G3: Genes, Genomes, Genetics

Joseph Heitman⁷  Soman N. Abraham⁴  Alice Alma C. Bungay²  Fitz Gerald S. Silao³  Jing Zhang⁶  Dawn A. Thompson⁸  Ursela G. Bigol¹  Ying-Lien Chen⁷  Jay H. Konieczka⁸  Marilou G. Nicolas⁹  Aviv Regev⁵  Deborah J. Springer⁷  Samantha E. Bowen⁷ 

[1] Environment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig City, 1631 PhilippinesEnvironment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig City, 1631 PhilippinesEnvironment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig City, 1631 Philippines;Department of Microbiology and Parasitology, University of Perpetual Help–Dr. Jose G. Tamayo Medical University, Biñan, Laguna, 4024 PhilippinesNational Institutes of Health, University of the Philippines, Manila, PhilippinesDepartment of Microbiology and Parasitology, University of Perpetual Help–Dr. Jose G. Tamayo Medical University, Biñan, Laguna, 4024 PhilippinesDepartment of Microbiology and Parasitology, University of Perpetual Help–Dr. Jose G. Tamayo Medical University, Biñan, Laguna, 4024 PhilippinesNational Institutes of Health, University of the Philippines, Manila, PhilippinesNational Institutes of Health, University of the Philippines, Manila, PhilippinesDepartment of Microbiology and Parasitology, University of Perpetual Help–Dr. Jose G. Tamayo Medical University, Biñan, Laguna, 4024 PhilippinesNational Institutes of Health, University of the Philippines, Manila, Philippines;Department of Microbiology and Parasitology, University of Perpetual Help–Dr. Jose G. Tamayo Medical University, Biñan, Laguna, 4024 PhilippinesDepartment of Microbiology and Parasitology, University of Perpetual Help–Dr. Jose G. Tamayo Medical University, Biñan, Laguna, 4024 PhilippinesDepartment of Microbiology and Parasitology, University of Perpetual Help–Dr. Jose G. Tamayo Medical University, Biñan, Laguna, 4024 Philippines;Department of Molecular Genetics and MicrobiologyPathologyImmunology, Duke University Medical Center, Durham, North Carolina 27710Department of Molecular Genetics and MicrobiologyDepartment of Molecular Genetics and MicrobiologyPathologyImmunology, Duke University Medical Center, Durham, North Carolina 27710PathologyDepartment of Molecular Genetics and MicrobiologyPathologyImmunology, Duke University Medical Center, Durham, North Carolina 27710Immunology, Duke University Medical Center, Durham, North Carolina 27710Department of Molecular Genetics and MicrobiologyPathologyImmunology, Duke University Medical Center, Durham, North Carolina 27710;The Broad Institute of MIT & Harvard, Cambridge, Massachusetts 02142Environment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig City, 1631 PhilippinesThe Broad Institute of MIT & Harvard, Cambridge, Massachusetts 02142The Broad Institute of MIT & Harvard, Cambridge, Massachusetts 02142Environment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig City, 1631 PhilippinesEnvironment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig City, 1631 PhilippinesThe Broad Institute of MIT & Harvard, Cambridge, Massachusetts 02142Environment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig City, 1631 Philippines;Department of Chemistry, Duke University, Durham, North Carolina 27710Department of Chemistry, Duke University, Durham, North Carolina 27710Department of Chemistry, Duke University, Durham, North Carolina 27710;Department of Molecular Genetics and MicrobiologyDepartment of Molecular Genetics and MicrobiologyDepartment of Molecular Genetics and Microbiology;The Broad Institute of MIT & Harvard, Cambridge, Massachusetts 02142The Broad Institute of MIT & Harvard, Cambridge, Massachusetts 02142The Broad Institute of MIT & Harvard, Cambridge, Massachusetts 02142;National Institutes of Health, University of the Philippines, Manila, PhilippinesNational Institutes of Health, University of the Philippines, Manila, PhilippinesNational Institutes of Health, University of the Philippines, Manila, Philippines

关键词: phosphatase;    calcium;    calmodulin;    Crz1;    Rcn1;    Rcn2;    thermotolerance;    cell wall integrity;    ER stress;    drug tolerance;    pH homeostasis;    urinary tract infection;    ocular infection;    virulence;   

DOI  :  10.1534/g3.112.002279

学科分类：生物科学（综合）

来源: Genetics Society of America

【 摘 要 】

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.

【 授权许可】

Unknown