title: Two Rac paralogs regulate polarized growth in the human fungal pathogen Cryptococcus neoformans.
abstract: A genome wide analysis of the human fungal pathogen Cryptococcus neoformans var. grubii has revealed a number of duplications of highly conserved genes involved in morphogenesis. Previously, we reported that duplicate Cdc42 paralogs provide C. neoformans with niche-specific responses to environmental stresses: Cdc42 is required for thermotolerance, while Cdc420 supports the formation of titan cells. The related Rho-GTPase Rac1 has been shown in C. neoformans var. neoformans to play a major role in filamentation and to share Cdc42/Cdc420 binding partners. Here we report the characterization of a second Rac paralog in C. neoformans, Rac2, and describe its overlapping function with the previously described CnRac, Rac1. Further, we demonstrate that the Rac paralogs play a primary role in polarized growth via the organization of reactive oxygen species and play only a minor role in the organization of actin. Finally, we provide preliminary evidence that pharmacological inhibitors of Rac activity and actin stability have synergistic activity.
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Elizabeth Ripley
authors.initials: ER
authors.lastname: Ballou
authors.forename: Kyla
authors.initials: K
authors.lastname: Selvig
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Narloch
authors.forename: Connie B
authors.initials: CB
authors.lastname: Nichols
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Alspaugh
mesh_terms: D000199:Actins / Q000378:metabolism; D003453:Cryptococcosis / Q000235:genetics / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000235:genetics* / Q000254:growth & development* / Q000472:pathogenicity; D006801:Humans; D009024:Morphogenesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000199:Actins; D017382:Reactive Oxygen Species; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
keywords: Cryptococcus neoformans; Hyphal growth; Paralogs; Polarization; ROS; Rac GTPase