title: Signaling through Lrg1, Rho1 and Pkc1 Governs Candida albicans Morphogenesis in Response to Diverse Cues.
abstract: The capacity to transition between distinct morphological forms is a key virulence trait for diverse fungal pathogens. A poignant example of a leading opportunistic fungal pathogen of humans for which an environmentally responsive developmental program underpins virulence is Candida albicans. C. albicans mutants that are defective in the transition between yeast and filamentous forms typically have reduced virulence. Although many positive regulators of C. albicans filamentation have been defined, there are fewer negative regulators that have been implicated in repression of filamentation in the absence of inducing cues. To discover novel negative regulators of filamentation, we screened a collection of 1,248 C. albicans homozygous transposon insertion mutants to identify those that were filamentous in the absence of inducing cues. We identified the Rho1 GAP Lrg1, which represses filamentous growth by stimulating Rho1 GTPase activity and converting Rho1 to its inactive, GDP-bound form. Deletion of LRG1 or introduction of a RHO1 mutation that locks Rho1 in constitutively active, GTP-bound state, leads to filamentation in the absence of inducing cues. Deletion of the Rho1 downstream effector PKC1 results in defective filamentation in response to diverse host-relevant inducing cues, including serum. We further established that Pkc1 is not required to sense filament-inducing cues, but its kinase activity is critical for the initiation of filamentous growth. Our genetic analyses revealed that Pkc1 regulates filamentation independent of the canonical MAP kinase cascade. Further, although Ras1 activation is not impaired in a pkc1Δ/pkc1Δ mutant, adenylyl cyclase activity is reduced, consistent with a model in which Pkc1 functions in parallel with Ras1 in regulating Cyr1 activation. Thus, our findings delineate a signaling pathway comprised of Lrg1, Rho1 and Pkc1 with a core role in C. albicans morphogenesis, and illuminate functional relationships that govern activation of a central transducer of signals that control environmental response and virulence programs.
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: Jinglin L
authors: http://orcid.org/0000-0001-7373-3449
authors: JL
authors: Xie
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors: Nora
authors: http://orcid.org/0000-0002-7227-9261
authors: N
authors: Grahl
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: Trevor
authors: http://orcid.org/0000-0002-5833-3049
authors: T
authors: Sless
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors: Michelle D
authors: MD
authors: Leach
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: Sang Hu
authors: http://orcid.org/0000-0003-0597-0623
authors: SH
authors: Kim
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors: Deborah A
authors: DA
authors: Hogan
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: Nicole
authors: N
authors: Robbins
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: Leah E
authors: LE
authors: Cowen
mesh_terms: D002176:Candida albicans / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D003599:Cytoskeleton / Q000235:genetics; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics; D009024:Morphogenesis / Q000235:genetics*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D005656:Fungal Proteins; D006023:Glycoproteins; D024101:Mitochondrial Proteins; D011493:Protein Kinase C; D018631:ras Proteins; D020741:rho GTP-Binding Proteins