title: Accumulation of specific sterol precursors targets a MAP kinase cascade mediating cell-cell recognition and fusion.
abstract: Sterols are vital components of eukaryotic cell membranes. Defects in sterol biosynthesis, which result in the accumulation of precursor molecules, are commonly associated with cellular disorders and disease. However, the effects of these sterol precursors on the metabolism, signaling, and behavior of cells are only poorly understood. In this study, we show that the accumulation of only ergosterol precursors with a conjugated double bond in their aliphatic side chain specifically disrupts cell-cell communication and fusion in the fungus Neurospora crassa Genetically identical germinating spores of this fungus undergo cell-cell fusion, thereby forming a highly interconnected supracellular network during colony initiation. Before fusion, the cells use an unusual signaling mechanism that involves the coordinated and alternating switching between signal sending and receiving states of the two fusion partners. Accumulation of only ergosterol precursors with a conjugated double bond in their aliphatic side chain disrupts this coordinated cell-cell communication and suppresses cell fusion. These specific sterol precursors target a single ERK-like mitogen-activated protein (MAP) kinase (MAK-1)-signaling cascade, whereas a second MAP kinase pathway (MAK-2), which is also involved in cell fusion, is unaffected. These observations indicate that a minor specific change in sterol structure can exert a strong detrimental effect on a key signaling pathway of the cell, resulting in the absence of cell fusion.
authors.affiliation: Institut für Genetik, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Weichert
authors.affiliation: Institute of Microbiology, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lichius
authors.affiliation: Institut für Genetik, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Bert-Ewald
authors.initials: BE
authors.lastname: Priegnitz
authors.affiliation: Institut für Genetik, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Brandt
authors.affiliation: Institut für Genetik, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Gottschalk
authors.affiliation: Institut für Organische Chemie, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Thorben
authors.initials: T
authors.lastname: Nawrath
authors.affiliation: Institut für Organische Chemie, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Groenhagen
authors.affiliation: Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester M13 9NT, United Kingdom.
authors.forename: Nick D
authors.initials: ND
authors.lastname: Read
authors.affiliation: Institut für Organische Chemie, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.affiliation: Institut für Genetik, Technische Universität Braunschweig, 38106 Braunschweig, Germany; a.fleissner@tu-bs.de.
authors.forename: André
authors.initials: A
authors.lastname: Fleißner
mesh_terms: D015415:Biomarkers; D002450:Cell Communication; D002459:Cell Fusion; D004789:Enzyme Activation; D004875:Ergosterol / Q000737:chemistry / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D017930:Genes, Reporter; D025301:Hyphae / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009492:Neurospora crassa / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D051638:Ether-A-Go-Go Potassium Channels; D005656:Fungal Proteins; D047428:Protein Kinase Inhibitors; D013261:Sterols; D020928:Mitogen-Activated Protein Kinases; D004875:Ergosterol
keywords: MAP kinase signaling; Neurospora crassa; cell fusion; ergosterol; sterol biosynthesis