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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 ubp5 Δ 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-ubp5 Δ 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.

Deubiquitinase Ubp5 Is Required for the Growth and Pathogenicity of Cryptococcus gattii