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Eukaryotic Cell, January 2005, p. 190-201, Vol. 4, No. 1
1535-9778/05/$08.00+0     doi:10.1128/EC.4.1.190-201.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transcriptional Network of Multiple Capsule and Melanin Genes Governed by the Cryptococcus neoformans Cyclic AMP Cascade

Read Pukkila-Worley,1,2,{dagger} Quincy D. Gerrald,1,{dagger} Peter R. Kraus,1,3,4 Marie-Josée Boily,1,3,4 Matthew J. Davis,1 Steven S. Giles,1 Gary M. Cox,1,3 Joseph Heitman,1,2,3,4 and J. Andrew Alspaugh1,3*

Departments of Medicine,1 Molecular Genetics and Microbiology,3 Pharmacology and Cancer Biology,4 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina2

Received 4 October 2004/ Accepted 13 October 2004

Cryptococcus neoformans is an opportunistic human fungal pathogen that elaborates several virulence attributes, including a polysaccharide capsule and melanin pigments. A conserved G{alpha} protein/cyclic AMP (cAMP) pathway controls melanin and capsule production. To identify targets of this pathway, we used an expression profiling approach to define genes that are transcriptionally regulated by the G{alpha} protein Gpa1. This approach revealed that Gpa1 transcriptionally regulates multiple genes involved in capsule assembly and identified two additional genes with a marked dependence on Gpa1 for transcription. The first is the LAC1 gene, encoding the laccase enzyme that catalyzes a rate-limiting step in diphenol oxidation and melanin production. The second gene identified (LAC2) is adjacent to the LAC1 gene and encodes a second laccase that shares 75% nucleotide identity with LAC1. Similar to the LAC1 gene, LAC2 is induced in response to glucose deprivation. However, LAC2 basal transcript levels are much lower than those for LAC1. Accordingly, a lac2 mutation results in only a modest delay in melanin formation. LAC2 overexpression suppresses the melanin defects of gpa1 and lac1 mutants and partially restores virulence of these strains. These studies provide mechanistic insights into the regulation of capsule and melanin production by the C. neoformans cAMP pathway and demonstrate that multiple laccases contribute to C. neoformans melanin production and pathogenesis.

* Corresponding author. Mailing address: DUMC 3355, Durham, NC 27710. Phone: (919) 684-0045. Fax: (919) 684-8902. E-mail: andrew.alspaugh{at}duke.edu.

{dagger} These authors contributed equally to the manuscript.

Eukaryotic Cell, January 2005, p. 190-201, Vol. 4, No. 1
1535-9778/05/$08.00+0     doi:10.1128/EC.4.1.190-201.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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