Melanin targets LC3-associated phagocytosis (LAP): A novel pathogenetic mechanism in fungal disease |
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Authors: | Georgios Chamilos Tonia Akoumianaki Irene Kyrmizi Axel Brakhage Anne Beauvais Jean-Paul Latge |
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Institution: | 1. Department of Medicine, University of Crete, Heraklion, Greece;2. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Crete, Greece;3. Department of Molecular and Applied Microbiology, Leibniz-Institute for Natural Product Research and Infection Biology (HKI) and Friedrich Schiller University, Jena, Germany;4. Unité des Aspergillus, and Plateforme de Microscopie electronique Institut Pasteur, Paris, France |
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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. |
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Keywords: | Aspergillus autophagy fungi LAP LC3-associated phagocytosis melanin NADPH oxidase p22phox |
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