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Eukaryotic Cell, January 2005, p. 202-208, Vol. 4, No. 1
1535-9778/05/$08.00+0     doi:10.1128/EC.4.1.202-208.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Distinct Stress Responses of Two Functional Laccases in Cryptococcus neoformans Are Revealed in the Absence of the Thiol-Specific Antioxidant Tsa1

Tricia A. Missall,1 Jason M. Moran,1,2 John A. Corbett,1,2 and Jennifer K. Lodge1,2*

Edward A. Doisy Department of Biochemistry and Molecular Biology,1 Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri2

Received 5 November 2004/ Accepted 11 November 2004

Laccases are thought to be important to the virulence of many fungal pathogens by producing melanin, a presumed oxygen radical scavenger. A laccase in Cryptococcus neoformans has been shown to synthesize melanin and contributes to the virulence and the survival in macrophages of this fungal pathogen. One C. neoformans laccase gene, LAC1, previously called CNLAC1, has been extensively studied, and we describe a homologous gene, LAC2, that is found 8 kb away from LAC1 in the genome. In this study we report a role for both laccases, in addition to the thiol peroxidase, Tsa1, in oxidative and nitrosative stress resistance mechanisms of C. neoformans. With use of real-time PCR, similar changes in expression of the two laccase genes occur in response to oxidative and nitrosative stresses, but only the regulation of the LAC2 gene during stress is influenced by Tsa1. Both laccases contribute to melanin production using L-dopa as a substrate and are differentially localized in the cell based on green fluorescent protein fusions. A single deletion of either LAC1 or LAC2 alone had no effect on sensitivity to H2O2 or nitric oxide. However, deletion of either LAC1 or LAC2 in combination with a TSA1 deletion resulted in a slight peroxide sensitivity, and a lac2{Delta} tsa1{Delta} deletion strain was sensitive to nitric oxide stress. In addition, the deletion of both laccases reduces survival of C. neoformans in primary macrophages. Based on our expression and functional analysis, we propose a novel model for the interaction of these two systems, which are both important for virulence.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. Phone: (314) 977-9217. Fax: (314) 977-9205. E-mail: lodgejk{at}slu.edu.

Eukaryotic Cell, January 2005, p. 202-208, Vol. 4, No. 1
1535-9778/05/$08.00+0     doi:10.1128/EC.4.1.202-208.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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