The stress responsive and morphologically regulated hsp90 gene from Paracoccidioides brasiliensis is essential to cell viability.
BACKGROUND
Paracoccidioides brasiliensis is a dimorphic fungus that causes the most prevalent systemic mycosis in Latin America. The response to heat shock is involved in pathogenesis, as this pathogen switches from mycelium to yeast forms in a temperature dependent fashion that is essential to establish infection. HSP90 is a molecular chaperone that helps in the folding and stabilization of selected polypeptides. HSP90 family members have been shown to present important roles in fungi, especially in the pathogenic species, as an immunodominant antigen and also as a potential antifungal therapeutic target.


RESULTS
In this work, we decided to further study the Pbhsp90 gene, its expression and role in cell viability because it plays important roles in fungal physiology and pathogenesis. Thus, we have sequenced a Pbhsp90 cDNA and shown that this gene is present on the genome as a single copy. We have also confirmed its preferential expression in the yeast phase and its overexpression during dimorphic transition and oxidative stress. Treatment of the yeast with the specific HSP90 inhibitors geldanamycin and radicicol inhibited growth at 2 and 10 microM, respectively.


CONCLUSIONS
The data confirm that the Pbhsp90 gene encodes a morphologically regulated and stress-responsive protein whose function is essential to cell viability of this pathogen. This work also enforces the potential of HSP90 as a target for antifungal therapies, since the use of HSP90 inhibitors is lethal to the P. brasiliensis yeast cells in a dose-responsive manner.
Nicola
André M
AM
Department of Cell Biology, University of Brasília, Brazil. anicola@aecom.yu.edu
Andrade
Rosângela V
RV
Dantas
Alessandra S
AS
Andrade
Patrícia A
PA
Arraes
Fabrício B M
FB
Fernandes
Larissa
L
Silva-Pereira
Ildinete
I
Felipe
Maria Sueli S
MS
D000595:Amino Acid Sequence; D016227:Benzoquinones / Q000494:pharmacology; D002470:Cell Survival; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000235:genetics*; D010228:Paracoccidioides / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016415:Sequence Alignment
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; C035359:monorden; C001277:geldanamycin