The CgHaa1-Regulon Mediates Response and Tolerance to Acetic Acid Stress in the Human Pathogen Candida glabrata.
To thrive in the acidic vaginal tract, Candida glabrata has to cope with high concentrations of acetic acid. The mechanisms underlying C. glabrata tolerance to acetic acid at low pH remain largely uncharacterized. In this work, the essential role of the CgHaa1 transcription factor (encoded by ORF CAGL0L09339g) in the response and tolerance of C. glabrata to acetic acid is demonstrated. Transcriptomic analysis showed that CgHaa1 regulates, directly or indirectly, the expression of about 75% of the genes activated under acetic acid stress. CgHaa1-activated targets are involved in multiple physiological functions including membrane transport, metabolism of carbohydrates and amino acids, regulation of the activity of the plasma membrane H+-ATPase, and adhesion. Under acetic acid stress, CgHaa1 increased the activity and the expression of the CgPma1 proton pump and contributed to increased colonization of vaginal epithelial cells by C. glabrata CgHAA1, and two identified CgHaa1-activated targets, CgTPO3 and CgHSP30, are herein demonstrated to be determinants of C. glabrata tolerance to acetic acid. The protective effect of CgTpo3 and of CgHaa1 was linked to a role of these proteins in reducing the accumulation of acetic acid inside C. glabrata cells. In response to acetic acid stress, marked differences were found in the regulons controlled by CgHaa1 and by its S. cerevisiae ScHaa1 ortholog, demonstrating a clear divergent evolution of the two regulatory networks. The results gathered in this study significantly advance the understanding of the molecular mechanisms underlying the success of C. glabrata as a vaginal colonizer.
Department of Bioengineering, Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Portugal.
Ruben T
RT
Bernardo
Department of Bioengineering, Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Portugal.
Diana V
DV
Cunha
School of Biomolecular and Biomedical Sciences, Conway Institute, University College of Dublin, Belfield, Dublin 4, Ireland.
Can
C
Wang
Centre of Biological Engineering, University of Minho, 4710-057 Braga, Portugal.
Leonel
L
Pereira
Centre of Biological Engineering, University of Minho, 4710-057 Braga, Portugal.
Sónia
S
Silva
Department of Bioengineering, Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Portugal.
Sara B
SB
Salazar
School of Biomolecular and Biomedical Sciences, Conway Institute, University College of Dublin, Belfield, Dublin 4, Ireland.
Markus S
MS
Schröder
Medical Mycology Research Center, Chiba University, Chuo-ku, 260-8673, Japan.
Michiyo
M
Okamoto
Medical Mycology Research Center, Chiba University, Chuo-ku, 260-8673, Japan.
Azusa
A
Takahashi-Nakaguchi
Medical Mycology Research Center, Chiba University, Chuo-ku, 260-8673, Japan.
Hiroji
H
Chibana
Department of Electronic and Information Engineering, Suzuka National College of Technology, Unver, Mie 510-0294, Japan.
Toshihiro
T
Aoyama
Department of Bioengineering, Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Portugal.
Isabel
I
Sá-Correia
Centre of Biological Engineering, University of Minho, 4710-057 Braga, Portugal.
Joana
J
Azeredo
School of Biomolecular and Biomedical Sciences, Conway Institute, University College of Dublin, Belfield, Dublin 4, Ireland.
Geraldine
G
Butler
Department of Bioengineering, Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Portugal nuno.mira@tecnico.ulisboa.pt.
Nuno Pereira
NP
Mira
D019342:Acetic Acid / Q000633:toxicity; D041221:Candida glabrata / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D002177:Candidiasis / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D019143:Evolution, Molecular; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics; D050890:HSP30 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D026901:Membrane Transport Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D014621:Vagina / Q000378:metabolism / Q000382:microbiology
D005656:Fungal Proteins; D050890:HSP30 Heat-Shock Proteins; C439059:Haa1 protein, S cerevisiae; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D019342:Acetic Acid
Candida glabrata; CgHaa1; acetic acid; vaginal candidiasis; vaginal dysbiosis