title: Melanin targets LC3-associated phagocytosis (LAP): A novel pathogenetic mechanism in fungal disease.
abstract: Intracellular swelling of conidia of the major human airborne fungal pathogen Aspergillus fumigatus results in surface exposure of immunostimulatory pathogen-associated molecular patterns (PAMPs) and triggers activation of a specialized autophagy pathway called LC3-associated phagocytosis (LAP) to promote fungal killing. We have recently discovered that, apart from PAMPs exposure, cell wall melanin removal during germination of A. fumigatus is a prerequisite for activation of LAP. Importantly, melanin promotes fungal pathogenicity via targeting LAP, as a melanin-deficient A. fumigatus mutant restores its virulence upon conditional inactivation of Atg5 in hematopoietic cells of mice. Mechanistically, fungal cell wall melanin selectively excludes the CYBA/p22phox subunit of NADPH oxidase from the phagosome to inhibit LAP, without interfering with signaling regulating cytokine responses. Notably, inhibition of LAP is a general property of melanin pigments, a finding with broad physiological implications.
authors.affiliation: a Department of Medicine , University of Crete , Heraklion , Greece.|b Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology , Heraklion , Crete , Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
authors.affiliation: a Department of Medicine , University of Crete , Heraklion , Greece.
authors.forename: Tonia
authors.initials: T
authors.lastname: Akoumianaki
authors.affiliation: a Department of Medicine , University of Crete , Heraklion , Greece.|b Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology , Heraklion , Crete , Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Kyrmizi
authors.affiliation: c Department of Molecular and Applied Microbiology , Leibniz-Institute for Natural Product Research and Infection Biology (HKI) and Friedrich Schiller University , Jena , Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Brakhage
authors.affiliation: d Unité des Aspergillus, and Plateforme de Microscopie electronique Institut Pasteur , Paris , France.
authors.forename: Anne
authors.initials: A
authors.lastname: Beauvais
authors.affiliation: d Unité des Aspergillus, and Plateforme de Microscopie electronique Institut Pasteur , Paris , France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latge
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus; D006801:Humans; D008543:Melanins / Q000378:metabolism*; D009181:Mycoses / Q000378:metabolism* / Q000382:microbiology; D010587:Phagocytosis / Q000502:physiology*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D008543:Melanins
keywords: Aspergillus; LAP; LC3-associated phagocytosis; NADPH oxidase; autophagy; fungi; melanin; p22phox