EC Accepts, published online ahead of print on 9 October 2009

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Eukaryotic Cell doi:10.1128/EC.00256-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulatory diversity of TUP1 in Cryptococcus neoformans.

Hyeseung Lee, Yun C. Chang, Ashok Varma, and Kyung J. Kwon-Chung^*

Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA

^* To whom correspondence should be addressed. Email: june_kwon-chung{at}nih.gov.

Cryptococcus neoformans serotype A strains, the major cause of cryptococcosis, are distributed world-wide while serotype D strains are more concentrated in Central Europe. We have previously shown that deletion of the global regulator TUP1 in serotype D isolates results in a novel peptide-mediated density-dependent growth phenotype that mimics quorum sensing not known to exist in other fungi. Unlike tup1 strains of serotype D, the density-dependent growth phenotype was found to be absent in tup1 strains of serotype A which had been derived from several different genetic clusters. Serotype A H99 tup1 strain showed slight retardation in the growth rate when compared to tup1 strains of serotype D but the mating efficiency was found to be similar in both serotypes. Deletion of TUP1 in the H99 strain resulted in significantly enhanced capsule production, defective melanin formation, and also revealed a unique regulatory role of the gene in maintaining iron/copper homeostasis. Differential expression of various genes involved in capsule formation and iron/copper homeostasis was observed between wild type and the tup1 strains of H99. Furthermore, the tup1 strain of H99 displayed pleiotropic effects which included sensitivity to SDS, susceptibility to fluconazole, and attenuated virulence. These results demonstrate that the global regulator, TUP1, has pathobiological significance and plays both conserved and distinct roles between serotype A and D strains of C. neoformans.