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Vol. 16, Issue 5, 2285-2300, May 2005
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* Department of Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710;
Department of Medicine, Duke University Medical Center, Durham, NC 27710;
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; and
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710
Submitted November 11, 2004;
Accepted February 16, 2005
Monitoring Editor: Charles Boone
The human pathogenic fungus Cryptococcus neoformans has diverged from a common ancestor into three biologically distinct varieties or sibling species over the past 10–40 million years. During evolution of these divergent forms, serotype A C. neoformans var. grubii has emerged as the most virulent and cosmopolitan pathogenic clade. Therefore, understanding how serotype A C. neoformans is distinguished from less successful pathogenic serotypes will provide insights into the evolution of fungal virulence. Here we report that the structurally conserved Pbs2-Hog1 MAP kinase cascade has been specifically recruited as a global regulator to control morphological differentiation and virulence factors in the highly virulent serotype A H99 clinical isolate, but not in the laboratory-generated and less virulent serotype D strain JEC21. The mechanisms of Hog1 regulation are strikingly different between the two strains, and the phosphorylation kinetics and localization pattern of Hog1 are opposite in H99 compared with JEC21 and other yeasts. The unique Hog1 regulatory pattern observed in the H99 clinical isolate is widespread in serotype A strains and is also present in some clinical serotype D isolates. Serotype A hog1
and pbs2 mutants are attenuated in virulence, further underscoring the role of the Pbs2-Hog1 MAPK cascade in the pathogenesis of cryptococcosis.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Joseph Heitman (heitm001{at}duke.edu).
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