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Vol. 19, Issue 5, 2251-2266, May 2008

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The Yak1 Kinase Is Involved in the Initiation and Maintenance of Hyphal Growth in Candida albicans

Sophie Goyard^*, Philipp Knechtle^*,, Murielle Chauvel^*, Adeline Mallet, Marie-Christine Prévost, Caroline Proux, Jean-Yves Coppée, Patrick Schwartz^||, Françoise Dromer^||, Hyunsook Park^¶, Scott G. Filler^¶, Guilhem Janbon^||, and Christophe d'Enfert^*

*Unité Biologie et Pathogénicité Fongiques, Institut National de la Recherche Agronomique USC2019, Plate-forme de Microscopie Ultrastructurale, Plate-Forme 2-Puces à ADN, Pasteur Génopole Ile-de-France, and ^||Unité de Mycologie Moléculaire, Centre National de la Recherche Scientifique URA3012, Institut Pasteur, Paris, France; ^¶Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, and David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1737

Submitted September 24, 2007; Revised February 20, 2008; Accepted February 27, 2008
Monitoring Editor: Daniel Lew

Members of the dual-specificity tyrosine-phosphorylated and regulated kinase (DYRK) family perform a variety of functions in eukaryotes. We used gene disruption, targeted pharmacologic inhibition, and genome-wide transcriptional profiling to dissect the function of the Yak1 DYRK in the human fungal pathogen Candida albicans. C. albicans strains with mutant yak1 alleles showed defects in the yeast-to-hypha transition and in maintaining hyphal growth. They also could not form biofilms. Despite their in vitro filamentation defect, C. albicans yak1/yak1 mutants remained virulent in animal models of systemic and oropharyngeal candidiasis. Transcriptional profiling showed that Yak1 was necessary for the up-regulation of only a subset of hypha-induced genes. Although downstream targets of the Tec1 and Bcr1 transcription factors were down-regulated in the yak1/yak1 mutant, TEC1 and BCR1 were not. Furthermore, 63% of Yak1-dependent, hypha-specific genes have been reported to be negatively regulated by the transcriptional repressor Tup1 and inactivation of TUP1 in the yak1/yak1 mutant restored filamentation, suggesting that Yak1 may function upstream of Tup1 in governing hyphal emergence and maintenance.

Present address: Evolva SA, Hagmattstrasse 6, 4123 Allschwil, Switzerland.

Address correspondence to: Christophe d'Enfert (denfert{at}pasteur.fr)

Abbreviations used: 1-NMPP1, 4-amino-1-(tert-butyl)-3-(1'-naphthylmethyl)pyrazolo-(3,4-d)-pyrimidine; DYRK, dual-specificity tyrosine-phosphorylated and regulated kinase; PKA, cAMP-dependent protein kinase.