title: Pleiotropic roles of the Msi1-like protein Msl1 in Cryptococcus neoformans.
abstract: Msi1-like (MSIL) proteins contain WD40 motifs and have a pleiotropic cellular function as negative regulators of the Ras/cyclic AMP (cAMP) pathway and components of chromatin assembly factor 1 (CAF-1), yet they have not been studied in fungal pathogens. Here we identified and characterized an MSIL protein, Msl1, in Cryptococcus neoformans, which causes life-threatening meningoencephalitis in humans. Notably, Msl1 plays pleiotropic roles in C. neoformans in both cAMP-dependent and -independent manners largely independent of Ras. Msl1 negatively controls antioxidant melanin production and sexual differentiation, and this was repressed by the inhibition of the cAMP-signaling pathway. In contrast, Msl1 controls thermotolerance, diverse stress responses, and antifungal drug resistance in a Ras/cAMP-independent manner. Cac2, which is the second CAF-1 component, appears to play both redundant and distinct functions compared to the functions of Msl1. Msl1 is required for the full virulence of C. neoformans. Transcriptome analysis identified a group of Msl1-regulated genes, which include stress-related genes such as HSP12 and HSP78. In conclusion, this study demonstrates pleiotropic roles of Msl1 in the human fungal pathogen C. neoformans, providing insight into a potential novel antifungal therapeutic target.
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, Yonsei University, Seoul, South Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Yang
authors.forename: Shinae
authors.initials: S
authors.lastname: Maeng
authors.forename: Anna K
authors.initials: AK
authors.lastname: Strain
authors.forename: Anna
authors.initials: A
authors.lastname: Floyd
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nielsen
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
mesh_terms: D000818:Animals; D056504:Chromatin Assembly Factor-1 / Q000235:genetics / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058685:Genetic Pleiotropy; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000235:genetics; D008543:Melanins / Q000096:biosynthesis; D051379:Mice; D010802:Phylogeny; D012733:Sex Differentiation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
chemical_list: D056504:Chromatin Assembly Factor-1; D005656:Fungal Proteins; D006360:Heat-Shock Proteins; D008543:Melanins; D000242:Cyclic AMP; D018631:ras Proteins