Flotillin-dependent lipid-raft microdomains are required for functional phagolysosomes against fungal infections.

Schmidt F, Thywißen A, Goldmann M, Cunha C, Cseresnyés Z, Schmidt H, Rafiq M, Galiani S, Gräler MH, Chamilos G, Lacerda JF, Campos Jr A, Eggeling C, Figge MT, Heinekamp T, Filler SG, Carvalho A, Brakhage AA (2020) Flotillin-dependent lipid-raft microdomains are required for functional phagolysosomes against fungal infections. Cell Rep 32(7), 108017.

Abstract

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 the phagolysosomal membrane of macrophages. Genetic deletion of the lipidraft chaperons flotillin-1 and flotillin-2 demonstrate that the assembly of both major defense complexes vATPase and NADPH oxidase on the phagolysosomal membrane requires lipid rafts. Furthermore, we discovered a new virulence mechanism leading to the dysregulation of lipid-raft formation by melanized wild-type conidia of the important human-pathogenic fungus Aspergillus fumigatus. This results in reduced phagolysosomal acidification. Phagolysosomes with ingested melanized conidia contain a reduced amount of free Ca2+ ions as compared to phagolysosomes with melanin-free conidia. In agreement with a role of Ca2+ for generation of functional lipid rafts, we show that Ca2+-dependent calmodulin activity is required for lipid-raft formation on the phagolysosome. We identified a single nucleotide polymorphism in the human FLOT1 gene that results in heightened susceptibility for invasive aspergillosis in hematopoietic stem-cell transplant recipients. Collectively, flotillin-dependent lipid rafts on the phagolysosomal membrane play an essential role in protective antifungal immunity in humans.

Leibniz-HKI-Authors

Axel A. Brakhage
Zoltán Cseresnyés
Marc Thilo Figge
Marie Goldmann
Thorsten Heinekamp
Muhammad Rafiq
Franziska Schmidt
Hella Schmidt
Andreas Thywißen

Identifier

doi: https://doi.org/10.1016/j.celrep.2020.108017

PMID: 32814035