title: Bypass of Candida albicans Filamentation/Biofilm Regulators through Diminished Expression of Protein Kinase Cak1.
abstract: Biofilm formation on implanted medical devices is a major source of lethal invasive infection by Candida albicans. Filamentous growth of this fungus is tied to biofilm formation because many filamentation-associated genes are required for surface adherence. Cell cycle or cell growth defects can induce filamentation, but we have limited information about the coupling between filamentation and filamentation-associated gene expression after cell cycle/cell growth inhibition. Here we identified the CDK activating protein kinase Cak1 as a determinant of filamentation and filamentation-associated gene expression through a screen of mutations that diminish expression of protein kinase-related genes implicated in cell cycle/cell growth control. A cak1 diminished expression (DX) strain displays filamentous growth and expresses filamentation-associated genes in the absence of typical inducing signals. In a wild-type background, expression of filamentation-associated genes depends upon the transcription factors Bcr1, Brg1, Efg1, Tec1, and Ume6. In the cak1 DX background, the dependence of filamentation-associated gene expression on each transcription factor is substantially relieved. The unexpected bypass of filamentation-associated gene expression activators has the functional consequence of enabling biofilm formation in the absence of Bcr1, Brg1, Tec1, Ume6, or in the absence of both Brg1 and Ume6. It also enables filamentous cell morphogenesis, though not biofilm formation, in the absence of Efg1. Because these transcription factors are known to have shared target genes, we suggest that cell cycle/cell growth limitation leads to activation of several transcription factors, thus relieving dependence on any one.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Carol A
authors.identifier: http://orcid.org/0000-0001-6261-3468
authors.initials: CA
authors.lastname: Woolford
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Katherine
authors.identifier: http://orcid.org/0000-0003-2232-0729
authors.initials: K
authors.lastname: Lagree
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Aleynikov
authors.affiliation: Department of Biological Sciences at the University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Hema
authors.identifier: http://orcid.org/0000-0001-8735-9734
authors.initials: H
authors.lastname: Adhikari
authors.affiliation: Departments of Medicine and Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Hiram
authors.identifier: http://orcid.org/0000-0002-6286-650X
authors.initials: H
authors.lastname: Sanchez
authors.affiliation: Department of Biological Sciences at the University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cullen
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Frederick
authors.initials: F
authors.lastname: Lanni
authors.affiliation: Departments of Medicine and Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Aaron P
authors.identifier: http://orcid.org/0000-0002-0868-4000
authors.initials: AP
authors.lastname: Mitchell
mesh_terms: D018441:Biofilms / Q000254:growth & development; D002176:Candida albicans / Q000235:genetics* / Q000254:growth & development; D002177:Candidiasis / Q000235:genetics / Q000382:microbiology; D002453:Cell Cycle / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D003599:Cytoskeleton / Q000235:genetics; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D025301:Hyphae / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D009024:Morphogenesis / Q000235:genetics*; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D005656:Fungal Proteins; D014157:Transcription Factors; D011494:Protein Kinases; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase