Studies on signal transduction pathway, which affect virulence of Candida albicans

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In response to various extracellular signals, the morphology of the human fungal pathogen Candida albicans switches from yeast to hyphal form. Here, we report that GPR1 encoding a putative G-protein coupled receptor and GPA2 encoding a Gα subunit are required for hyphal formation and morphogenesis in C.albicans. Mutants lacking Gpr1(gpr1/gpr1) or Gpa2(gpa2/gpa2) are defective in hyphal formation and morphogenesis on solid hyphal-inducing media. These phenotypic defects in solid cultures are suppressed by exogenously added dibutyryl-cAMP. Biochemical studies also reveal that GPR1 and GPA2 are required for a glucose-dependent increase in cellular cAMP. An epistasis analysis indicates that Gpr1 functions upstream of Gpa2 in the same signaling pathway, and a two-hybrid assay reveals that the carboxyl terminal tail of Gpr1 interacts with Gpa2. Moreover, expression levels of HWP1 and ECE1, which are cAMP-dependent hyphal-specific genes, are reduced in both mutant strains. These findings support a model that Gpr1 as well as Gpa2 regulates hyphal formation and morphogenesis in a cAMP-dependent manner. In contrast, GPR1 and GPA2 are not required for hyphal formation in liquid FBS medium. Furthermore, the gpr1l and the gpa2 mutant strains are fully virulent in a mouse infection. These findings suggest that Gpr1 and Gpa2 are involved in the glucose sensing machinery that regulates morphogenesis and hyphal formation in solid media via a cAMP-dependent mechanism, but they are not required for hyphal formation in liquid medium or during invasive candidiasis.