Protein kinase A subunits have distinct roles in pathogenesis of Candidaglabrata

The cyclic AMP (cAMP) dependent protein kinase A (PKA) pathway regulates divergent cellular processes, including growth, stress response, and pathogenicity in fungi. Although the PKA complex plays important roles in morphogenesis, biofilm formation, and virulence in several Candida species, its functions in non-dimorphic yeast Candida glabrata (Nakaseomyces glabratus) remain unclear.

Single and double gene deletion mutants of PKA subunits were generated. Phenotypic analyses were performed to evaluate growth, glycogen accumulation, stress responses, PKA substrate phosphorylation profiles, and biofilm formation. A murine model of invasive candidiasis was used to assess virulence.

Deletion of either catalytic subunit, Tpk1 or Tpk2, resulted in minimal phenotypic changes, indicating functional redundancy. In contrast, loss of the regulatory subunit BCY1 gene led to impaired growth, reduced glycogen accumulation, increased sensitivity to environmental stresses, and decreased biofilm formation, but enhanced virulence in murine model. The bcy1 tpk2 mutant exhibited phenotypes similar to the bcy1 mutant, suggesting that constitutively active Tpk1 is sufficient to drive these effects, potentially through reduced TPK2 expression. Furthermore, Tpk1 and Tpk2 contributed redundantly to virulence, while Bcy1 functioned as a negative regulator.

This study reveals distinct regulatory roles of the PKA complex in C. glabrata and highlight its contribution to fungal adaptation and pathogenicity.