title: Inhibition of CBLB protects from lethal Candida albicans sepsis.
abstract: Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wirnsberger
authors.affiliation: Medical University of Vienna, Max F. Perutz Laboratories (MFPL), Department of Medical Biochemistry, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Zwolanek
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Asaoka
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tortola
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Wimmer
authors.affiliation: Vienna Biocenter Core Facilities (VBCF), Vienna, Austria.
authors.forename: Anoop
authors.initials: A
authors.lastname: Kavirayani
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Fresser
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Fumiyo
authors.identifier: 0000-0003-0407-2768
authors.initials: F
authors.lastname: Ikeda
authors.affiliation: Medical University of Vienna, Max F. Perutz Laboratories (MFPL), Department of Medical Biochemistry, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Josef M
authors.identifier: 0000-0002-8194-3777
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015153:Blotting, Western; D002176:Candida albicans; D058365:Candidiasis, Invasive / Q000276:immunology*; D053181:Caspase 8; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D047468:Immunoprecipitation; D007668:Kidney; D037181:Lectins, C-Type / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010455:Peptides / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016133:Polymerase Chain Reaction; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D016207:Cytokines; D037181:Lectins, C-Type; D010455:Peptides; D017382:Reactive Oxygen Species; D050721:Proto-Oncogene Proteins c-cbl; C505526:Casp8 protein, mouse; D053181:Caspase 8