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Lipid rafts form signaling platforms on biological membranes with incompletely characterized role in immune response to infection. Here we report that lipid-raft microdomains are essential components of phagolysosomal membranes of macrophages and depend on flotillins. Genetic deletion of flotillins demonstrates that the assembly of both major defense complexes vATPase and NADPH oxidase requires membrane microdomains. Furthermore, we describe a virulence mechanism leading to dysregulation of membrane microdomains by melanized wild-type conidia of the important human-pathogenic fungus Aspergillus fumigatus resulting in reduced phagolysosomal acidification. We show that phagolysosomes with ingested melanized conidia contain a reduced amount of free Ca2+ ions and that inhibition of Ca2+-dependent calmodulin activity led to reduced lipid-raft formation. We identify a single-nucleotide polymorphism in the human FLOT1 gene resulting in heightened susceptibility for invasive aspergillosis in hematopoietic stem cell transplant recipients. Collectively, flotillin-dependent microdomains on the phagolysosomal membrane play an essential role in protective antifungal immunity. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Franziska Schmidt, Andreas Thywißen, Marie Goldmann, Cristina Cunha, Zoltán Cseresnyés, Hella Schmidt, Muhammad Rafiq, Silvia Galiani, Markus H Gräler, Georgios Chamilos, João F Lacerda, António Campos, Christian Eggeling, Marc Thilo Figge, Thorsten Heinekamp, Scott G Filler, Agostinho Carvalho, Axel A Brakhage. Flotillin-Dependent Membrane Microdomains Are Required for Functional Phagolysosomes against Fungal Infections. Cell reports. 2020 Aug 18;32(7):108017

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PMID: 32814035

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