Abstract
Ubiquitination is a reversible protein modification that influences various cellular processes in eukaryotic cells. Deubiquitinating enzymes remove ubiquitin, maintain ubiquitin homeostasis and regulate protein degradation via the ubiquitination pathway. Cryptococcus neoformans is an important basidiomycete pathogen that causes life-threatening meningoencephalitis primarily in the immunocompromised population. In order to understand the possible influence deubiquitinases have on growth and virulence of the model pathogenic yeast Cryptococcus neoformans, we generated deletion mutants of seven putative deubiquitinase genes. Compared to other deubiquitinating enzyme mutants, a ubp5Δ mutant exhibited severely attenuated virulence and many distinct phenotypes, including decreased capsule formation, hypomelanization, defective sporulation, and elevated sensitivity to several external stressors (such as high temperature, oxidative and nitrosative stresses, high salts, and antifungal agents). Ubp5 is likely the major deubiquitinating enzyme for stress responses in C. neoformans, which further delineates the evolutionary divergence of Cryptococcus from the model yeast S. cerevisiae, and provides an important paradigm for understanding the potential role of deubiquitination in virulence by other pathogenic fungi. Other putative deubiquitinase mutants (doa4Δ and ubp13Δ) share some phenotypes with the ubp5Δ mutant, illustrating functional overlap among deubiquitinating enzymes in C. neoformans. Therefore, deubiquitinating enzymes (especially Ubp5) are essential for the virulence composite of C. neoformans and provide an additional yeast survival and propagation advantage in the host.
Highlights
Cryptococcus neoformans is a very important basidiomycete fungal pathogen, which can cause life-threatening meningoencephalitis primarily among immunocompromised hosts
To appreciate the function of this in vivo regulated ubiquitination system, we focused on the importance of deubiquitinating enzymes (DUB) in C. neoformans disease
We identified 19 putative DUB proteins in the C. neoformans strain H99 genome belonging to four of five DUB subfamilies (UCH, ubiquitinspecific proteases (USPs), ovarian tumor proteases (OTUs), and JAB1/ MPN/Mov34 metalloenzymes (JAMMs)) by homology to known DUBs from S. cerevisiae and S. pombe
Summary
Cryptococcus neoformans is a very important basidiomycete fungal pathogen, which can cause life-threatening meningoencephalitis primarily among immunocompromised hosts. An outbreak of cryptococcal disease among immunocompetent humans and animals on Vancouver Island and the Pacific Northwest, USA since 1999 caused by Cryptococcus gattii (a species that is closely related to C. neoformans) emphasizes that this infection can break out of the classic opportunistic risk groups [3]. Due to its well-defined sexual cycle, robust animal models and molecular biology tools, C. neoformans has become an excellent model for the study of fungal pathogenesis [14,15]. These advances have confirmed the fact that fungal virulence is a very complicated phenotype. Identification of the essential complex regulatory mechanisms in control of the cryptococcal virulence composite and its networks will be helpful in identifying targets to abrogate disease caused by C. neoformans
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