title: The F-Box protein Fbp1 regulates sexual reproduction and virulence in Cryptococcus neoformans.
abstract: Cryptococcus neoformans is the leading cause of fungal meningitis in immunocomprised populations. Although extensive studies have been conducted on signal transduction pathways important for fungal sexual reproduction and virulence, how fungal virulence is regulated during infection is still not understood. In this study, we identified the F-box protein Fbp1, which contains a putative F-box domain and 12 leucine-rich repeats (LRR). Although fbp1 mutants showed normal growth and produced normal major virulence factors, such as melanin and capsule, Fbp1 was found to be essential for fungal virulence, as fbp1 mutants were avirulent in a murine systemic-infection model. Fbp1 is also important for fungal sexual reproduction. Basidiospore production was blocked in bilateral mating between fbp1 mutants, even though normal dikaryotic hyphae were observed during mating. In vitro assays of stress responses revealed that fbp1 mutants are hypersensitive to SDS, but not calcofluor white (CFW) or Congo red, indicating that Fbp1 may regulate cell membrane integrity. Fbp1 physically interacts with Skp1 homologues in both Saccharomyces cerevisiae and C. neoformans via its F-box domain, suggesting it may function as part of an SCF (Skp1, Cullins, F-box proteins) E3 ligase. Overall, our study revealed that the F-box protein Fbp1 is essential for fungal sporulation and virulence in C. neoformans, which likely represents a conserved novel virulence control mechanism that involves the SCF E3 ubiquitin ligase-mediated proteolysis pathway.
authors.affiliation: Public Health Research Institute, University of Medicine and Dentistry of New Jersey, ICPH Building Room W250H, 225 Warren Street, Newark, NJ 07103, USA.
authors.forename: Tong-Bao
authors.initials: TB
authors.lastname: Liu
authors.forename: Yina
authors.initials: Y
authors.lastname: Wang
authors.forename: Sabriya
authors.initials: S
authors.lastname: Stukes
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Xue
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D048750:Cell Nucleus Division / Q000235:genetics; D015169:Colony Count, Microbial; D003227:Conjugation, Genetic; D017124:Conserved Sequence; D003453:Cryptococcosis / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000472:pathogenicity* / Q000502:physiology; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D055786:Gene Knockout Techniques; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D010587:Phagocytosis; D011485:Protein Binding; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; D005656:Fungal Proteins; D044786:S-Phase Kinase-Associated Proteins; D037521:Virulence Factors