title: Deubiquitinase Ubp5 Is Required for the Growth and Pathogenicity of Cryptococcus gattii.
abstract: Cryptococcus gattii is a resurgent fungal pathogen that primarily infects immunocompetent hosts. Thus, it poses an increasingly significant impact on global public health; however, the mechanisms underlying its pathogenesis remain largely unknown. We conducted a detailed characterization of the deubiquitinase Ubp5 in the biology and virulence of C. gattii using the hypervirulent strain R265, and defined its properties as either distinctive or shared with C. neoformans. Deletion of the C. gattii Ubp5 protein by site-directed disruption resulted in a severe growth defect under both normal and stressful conditions (such as high temperature, high salt, cell wall damaging agents, and antifungal agents), similar to the effects observed in C. neoformans. However, unlike C. neoformans, the C. gattii ubp5Δ mutant displayed a slight enhancement of capsule and melanin production, indicating the evolutionary convergence and divergence of Ubp5 between these two sibling species. Attenuated virulence of the Cg-ubp5Δ mutant was not solely due to its reduced thermotolerance at 37°C, as shown in both worm and mouse survival assays. In addition, the assessment of fungal burden in mammalian organs further indicated that Ubp5 was required for C. gattii pulmonary survival and, consequently, extrapulmonary dissemination. Taken together, our work highlights the importance of deubiquitinase Ubp5 in the virulence composite of both pathogenic cryptococcal species, and it facilitates a better understanding of C. gattii virulence mechanisms.
authors.affiliation: Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Medical Mycology, Second Military Medical University, Shanghai, China.|Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Meng
authors.affiliation: PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.
authors.forename: Jiu
authors.initials: J
authors.lastname: Yi
authors.affiliation: PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.
authors.forename: Zhenzong
authors.initials: Z
authors.lastname: Fa
authors.affiliation: Shanghai Dermatology Hospital, Shanghai, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhao
authors.affiliation: PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Yang
authors.affiliation: PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Medical Mycology, Second Military Medical University, Shanghai, China.
authors.forename: Wan-Qing
authors.initials: WQ
authors.lastname: Liao
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D056285:Cryptococcus gattii / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity*; D005800:Genes, Fungal; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D000935:Antifungal Agents; D064570:Ubiquitin-Specific Proteases