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Nat Microbiol. 2018 Jul;3(7):791-803. doi: 10.1038/s41564-018-0167-x. Epub 2018 May 30.

Calcium sequestration by fungal melanin inhibits calcium-calmodulin signalling to prevent LC3-associated phagocytosis.

Author information

1
Department of Medicine, University of Crete, Heraklion, Crete, Greece.
2
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Crete, Greece.
3
3B's Research Group - Biomaterials, Biodegradables and Biomimetics, Guimarães, Portugal.
4
ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
5
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.
6
Department of Chemistry, University of Cincinnati/Agilent Technologies Metallomics Center of the Americas, University of Cincinnati, Cincinnati, OH, USA.
7
Department of Chemistry, University of Crete, Heraklion, Crete, Greece.
8
Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
9
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisbon, Portugal.
10
Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Lisbon, Portugal.
11
Serviço de Transplantação de Medula Óssea (STMO), Instituto Português de Oncologia do Porto, Porto, Portugal.
12
Department of Infectious Diseases, The University of Texas, MD Anderson Cancer Center, Austin, TX, USA.
13
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
14
INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France.
15
Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, DHU FIRE, Faculté de Médecine, Site Xavier Bichat, Paris, France.
16
Unité des Aspergillus, Institut Pasteur, Paris, France.
17
Department of Molecular and Applied Microbiology, Leibniz-Institute for Natural Product Research and Infection Biology (HKI) and Friedrich Schiller University, Jena, Germany.
18
Department of Medicine, University of Crete, Heraklion, Crete, Greece. hamilos@imbb.forth.gr.
19
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Crete, Greece. hamilos@imbb.forth.gr.

Abstract

LC3-associated phagocytosis (LAP) is a non-canonical autophagy pathway regulated by Rubicon, with an emerging role in immune homeostasis and antifungal host defence. Aspergillus cell wall melanin protects conidia (spores) from killing by phagocytes and promotes pathogenicity through blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of LAP. However, the signalling regulating LAP upstream of Rubicon and the mechanism of melanin-induced inhibition of this pathway remain incompletely understood. Herein, we identify a Ca2+ signalling pathway that depends on intracellular Ca2+ sources from endoplasmic reticulum, endoplasmic reticulum-phagosome communication, Ca2+ release from phagosome lumen and calmodulin (CaM) recruitment, as a master regulator of Rubicon, the phagocyte NADPH oxidase NOX2 and other molecular components of LAP. Furthermore, we provide genetic evidence for the physiological importance of Ca2+-CaM signalling in aspergillosis. Finally, we demonstrate that Ca2+ sequestration by Aspergillus melanin inside the phagosome abrogates activation of Ca2+-CaM signalling to inhibit LAP. These findings reveal the important role of Ca2+-CaM signalling in antifungal immunity and identify an immunological function of Ca2+ binding by melanin pigments with broad physiological implications beyond fungal disease pathogenesis.

PMID:
29849062
DOI:
10.1038/s41564-018-0167-x

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