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Eukaryotic Cell, August 2004, p. 919-931, Vol. 3, No. 4
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.4.919-931.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Gpr1, a Putative G-Protein-Coupled Receptor, Regulates Morphogenesis and Hypha Formation in the Pathogenic Fungus Candida albicans

Takuya Miwa,1,{dagger} Yukinobu Takagi,2,{dagger} Makiko Shinozaki,2 Cheol-Won Yun,3 Wiley A. Schell,4 John R. Perfect,4,5 Hidehiko Kumagai,1,2 and Hisanori Tamaki1,2*

Division of Applied Life Sciences, Graduate School of Agriculture,1 Division of Integrated Life Sciences, Graduate School of Biostudies, Kyoto University, Kyoto, Japan,2 School of Life Sciences and Biotechnology, Korea University, Anam-Dong, Sungbuk-ku, Seoul, South Korea,3 Departments of Molecular Genetics and Microbiology,4 Medicine, Duke University Medical Center, Durham, North Carolina5

Received 6 March 2004/ Accepted 17 June 2004

In response to various extracellular signals, the morphology of the human fungal pathogen Candida albicans switches from yeast to hypha form. Here, we report that GPR1 encoding a putative G-protein-coupled receptor and GPA2 encoding a G{alpha} subunit are required for hypha formation and morphogenesis in C. albicans. Mutants lacking Gpr1 (gpr1/gpr1) or Gpa2 (gpa2/gpa2) are defective in hypha formation and morphogenesis on solid hypha-inducing media. These phenotypic defects in solid cultures are suppressed by exogenously added dibutyryl-cyclic AMP (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 hypha-specific genes, are reduced in both mutant strains. These findings support a model that Gpr1, as well as Gpa2, regulates hypha formation and morphogenesis in a cAMP-dependent manner. In contrast, GPR1 and GPA2 are not required for hypha formation in liquid fetal bovine serum (FBS) medium. Furthermore, the gpr1 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 hypha formation in solid media via a cAMP-dependent mechanism, but they are not required for hypha formation in liquid medium or during invasive candidiasis.

* Corresponding author. Mailing address: Division of Integrated Life Sciences, Graduate School of Biostudies, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan. Phone: 81-75-753-6278. Fax: 81-75-753-6275. E-mail: noritama{at}kais.kyoto-u.ac.jp.

{dagger} T.M. and Y.T. contributed equally to this study.

Eukaryotic Cell, August 2004, p. 919-931, Vol. 3, No. 4
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.4.919-931.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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