A cyclin protein governs the infectious and sexual life cycles of Cryptococcus neoformans

Abstract

Cell cycle is a fundamental process underlying growth and development in evolutionarily diverse organisms, including fungi. In human fungal pathogens, cell cycle control generally determines their life cycles, either in the environment or during infections. Thus, cell cycle components can potentially serve as important targets for the development of antifungal strategy against fungal infections. Here, in Cryptococcus neoformans, the most common cause of fatal fungal meningitis, we show that a previously uncharacterized B-type cyclin named Cbc1 is essential for both its infectious and sexual cycles. We reveal that Cbc1 coordinates various sexual differentiation and molecular processes, including meiosis. Especially, the absence of Cbc1 abolishes formation of sexual spores in C. neoformans, which are presumed infectious particles. Cbc1 is also required for the major Cryptococcus pathogenic attributes. Virulence assessment using the murine model of cryptococcosis revealed that the cbc1 mutant is avirulent. Together, our results provide an important insight into how C. neoformans employs shared cell cycle regulation to coordinate its infectious and sexual cycles, which are considered crucial for virulence evolution and the production of infectious spores.

Dynamic genome plasticity during unisexual reproduction in the human fungal pathogen Cryptococcus deneoformans

“…Deletion of CLB3 caused defects in stress resistance, melanin production, and capsule formation, and the deletion strain was avirulent in a mouse infection model [54,56]. Interestingly, different from the deletion mutants of the other five cell cycle regulating genes, deletion of CLB3 blocked basidium spore chain production during bisexual reproduction [54], suggesting that Clb3 plays a pivot role in sporogenesis during both modes of sexual reproduction in C. deneoformans.…”

“…In S. cerevisiae , CLB3 is a nonessential cyclin gene expressed during G2/M phase, activating Cdc28 and promoting G2/M phase transition [34]. In C. deneoformans , CLB3 was also not essential, and Pengjie Hu and colleagues have successfully deleted CLB3 utilizing a CRISPR-mediated transformation technique [50, 51]. Deletion of CLB3 caused defects in stress resistance, melanin production, and capsule formation, and the deletion strain was avirulent in a mouse infection model [50, 52].…”

“…In C. deneoformans , CLB3 was also not essential, and Pengjie Hu and colleagues have successfully deleted CLB3 utilizing a CRISPR-mediated transformation technique [50, 51]. Deletion of CLB3 caused defects in stress resistance, melanin production, and capsule formation, and the deletion strain was avirulent in a mouse infection model [50, 52]. In this study, suppression of CLB3 expression led to cell cycle arrest at G2/M phase, which is consistent with the phenotype observed for the deletion mutant, suggesting that Clb3 contributes to G2/M phase progression, a conserved role for Clb3 in S. cerevisiae [34, 50].…”

“…In S. cerevisiae, CLB3 is a nonessential cyclin gene expressed during G2/M phase, activating Cdc28 and promoting G2/M phase transition [34]. In C. deneoformans, CLB3 was also not essential, and Pengjie Hu and colleagues have successfully deleted CLB3 utilizing a CRISPR-mediated transformation technique [54,55].…”

Dynamic genome plasticity during unisexual reproduction in the human fungal pathogen Cryptococcus deneoformans

“…In S. cerevisiae, CLB3 is a nonessential cyclin gene expressed during G2/M phase, activating Cdc28 and promoting G2/M phase transition [34]. In C. deneoformans, CLB3 was also not essential, and Pengjie Hu and colleagues have successfully deleted CLB3 utilizing a CRISPR-mediated transformation technique [54,55]. Our failure in deleting this gene was likely due to the combinatory effect of low biolistic transformation efficiency and a severe defect in cytokinesis of the mutant.…”