Journal
NATURE MICROBIOLOGY
Volume 3, Issue 7, Pages 791-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41564-018-0167-x
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Funding
- Onassis Foundation under the 'Special Grant and Support Program for Scholars' Association Members' [R ZM 003-1/2016-2017]
- Greek State Scholarship Foundation
- Hellenic General Secretariat for Research and Technology-Excellence program (ARISTEIA)
- Institut Merieux
- European Community's Seventh Framework Programme (FP7) [260338 ALLFUN, ANR-10-BLAN-1309 HYDROPHOBIN]
- Association Vaincre La Mucoviscidose [RF20140501052/1/1/141]
- project FROnTHERA [NORTE-01-0145-FEDER-000023]
- Northern Portugal Regional Operational Programme (NORTE 2020), under European Regional Development Fund (ERDF)
- Fundacao para a Ciencia e Tecnologia (FCT) project SPARTAN through PIDDAC Program [PTDC/CTM-BIO/4388/2014]
- NORTE, under ERDF [NORTE-01-0145-FEDER-000013]
- FCT [IF/00735/2014, SFRH/BPD/96176/2013]
- NIH [AI-106269]
- Division of Intramural Research (DIR), NIAID, NIH
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000657] Funding Source: NIH RePORTER
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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.
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