title: Caspofungin exposure alters the core septin AspB interactome of Aspergillus fumigatus.
abstract: Aspergillus fumigatus, the main etiological agent of invasive aspergillosis, is a leading cause of death in immunocompromised patients. Septins, a conserved family of GTP-binding proteins, serve as scaffolding proteins to recruit enzymes and key regulators to different cellular compartments. Deletion of the A. fumigatus septin aspB increases susceptibility to the echinocandin antifungal caspofungin. However, how AspB mediates this response to caspofungin is unknown. Here, we characterized the AspB interactome under basal conditions and after exposure to a clinically relevant concentration of caspofungin. While A. fumigatus AspB interacted with 334 proteins, including kinases, cell cycle regulators, and cell wall synthesis-related proteins under basal growth conditions, caspofungin exposure altered AspB interactions. A total of 69 of the basal interactants did not interact with AspB after exposure to caspofungin, and 54 new interactants were identified following caspofungin exposure. We generated A. fumigatus deletion strains for 3 proteins (ArpB, Cyp4, and PpoA) that only interacted with AspB following exposure to caspofungin that were previously annotated as induced after exposure to antifungal agents, yet only PpoA was implicated in the response to caspofungin. Taken together, we defined how the septin AspB interactome is altered in the presence of a clinically relevant antifungal.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States.
authors.forename: José M
authors.initials: JM
authors.lastname: Vargas-Muñiz
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States.
authors.forename: Hilary
authors.initials: H
authors.lastname: Renshaw
authors.affiliation: Duke Proteomics and Metabolomics Core Facility, Center for Genomic and Computational Biology, Duke University, Durham, NC, United States.
authors.forename: Greg
authors.initials: G
authors.lastname: Waitt
authors.affiliation: Duke Proteomics and Metabolomics Core Facility, Center for Genomic and Computational Biology, Duke University, Durham, NC, United States.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Soderblom
authors.affiliation: Duke Proteomics and Metabolomics Core Facility, Center for Genomic and Computational Biology, Duke University, Durham, NC, United States.
authors.forename: M Arthur
authors.initials: MA
authors.lastname: Moseley
authors.affiliation: U.S. Forest Service, Northern Research Station, Center for Forest Mycology Research, Madison, WI, United States; Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Palmer
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Praveen R
authors.initials: PR
authors.lastname: Juvvadi
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States.
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States; Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States. Electronic address: bill.steinbach@duke.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Steinbach
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000077336:Caspofungin; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects*; D058112:Septins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D058112:Septins; D000077336:Caspofungin
keywords: AspB; Aspergillus fumigatus; Caspofungin; Interactome; Septins