Abstract
Cryptococcus neoformans is an opportunistic yeast-like pathogen that mainly infects immunocompromised individuals and causes fatal meningitis. Sexual reproduction can promote the exchange of genetic material between different strains of C. neoformans, which is one of the reasons leading to the emergence of highly pathogenic and drug-resistant strains of C. neoformans. Although much research has been done on the regulation mechanism of Cryptococcus sexual reproduction, there are few studies on the sexual reproduction regulation of Cryptococcus by the ubiquitin-proteasome system. This study identified an F-box protein, Cdc4, which contains a putative F-box domain and eight WD40 domains. The expression pattern analysis showed that the CDC4 gene was expressed in various developmental stages of C. neoformans, and the Cdc4 protein was localized in the nucleus of cryptococcal cells. In vitro stress responses assays showed that the CDC4 overexpression strains are sensitive to SDS and MMS but not Congo red, implying that Cdc4 may regulate the cell membrane integrity and repair of DNA damage of C. neoformans. Fungal virulence assay showed that although the cdc4Δ mutant grows normally and can produce typical virulence factors such as capsule and melanin, the cdc4Δ mutant completely loses its pathogenicity in a mouse systemic-infection model. Fungal mating assays showed that Cdc4 is also essential for fungal sexual reproduction in C. neoformans. Although normal mating hyphae were observed during mating, the basidiospores’ production was blocked in bilateral mating between cdc4Δ mutants. Fungal nuclei development assay showed that the nuclei failed to undergo meiosis after fusion inside the basidia during the bilateral mating of cdc4Δ mutants, indicating that Cdc4 is critical to regulating meiosis during cryptococcal mating. In summary, our study revealed that the F-box protein Cdc4 is critical for fungal virulence and sexual reproduction in C. neoformans.
Highlights
Cryptococcus neoformans is an encapsulated yeast pathogen that can infect the central nervous system (CNS) to cause fatal fungal meningitis in immunocompromised patients, resulting in hundreds of thousands of deaths each year (Casadevall and Perfect, 1998; Park et al, 2009; Rajasingham et al, 2017)
Our previous study identified an F-box protein Fbp1 in C. neoformans, and functional analysis revealed that Fbp1 plays an essential role in sexual reproduction and virulence in C. neoformans (Liu et al, 2011; Liu and Xue, 2014)
Given that the F-box protein Fbp1 plays an important role in C. neoformans, we scanned the genome sequence of C. neoformans strain H99 and identified 19 proteins (Table 1) that contain the F-box domain in the H99 genome database
Summary
Cryptococcus neoformans is an encapsulated yeast pathogen that can infect the central nervous system (CNS) to cause fatal fungal meningitis in immunocompromised patients, resulting in hundreds of thousands of deaths each year (Casadevall and Perfect, 1998; Park et al, 2009; Rajasingham et al, 2017). Grr homologs such as Grr in Candida albicans (Butler et al, 2006), GrrA in Aspergillus aspergillus (Krappmann et al, 2006), and the Fbp in Gibberella zeae (Han et al, 2007) have been functionally studied Another F-box protein, Cdc, has been studied in S. cerevisiae (Feldman et al, 1997; Orlicky et al, 2003) and C. albicans (Atir-Lande et al, 2005; Shieh et al, 2005), which have been shown to be associated with the cell cycle and morphological development of fungi. Our previous studies identified an F-box protein Fbp that is essential for fungal virulence in C. neoformans (Liu et al, 2011; Liu and Xue, 2014). CNAG_05450 CNAG_05454 CNAG_05773 CNAG_05874 CNAG_06382 CNAG_06722 CNAG_07482 CNAG_07551 CNAG_07702
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