Pleiotropic roles of the Msi1-like protein Msl1 in Cryptococcus neoformans.
Eukaryot Cell, 2012/12;11(12):1482-95.
Yang DH[1], Maeng S, Strain AK, Floyd A, Nielsen K, Heitman J, Bahn YS
Affiliations
PMID: 23042129DOI: 10.1128/EC.00261-12
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.
MeSH terms
Animals; Chromatin Assembly Factor-1; Cryptococcus neoformans; Cyclic AMP; Female; Fungal Proteins; Genetic Pleiotropy; Heat-Shock Proteins; Heat-Shock Response; Melanins; Mice; Phylogeny; Sex Differentiation; Transcriptome; Up-Regulation; ras Proteins
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