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

Irene Kyrmizi, Helena Ferreira, Agostinho Carvalho, Julio Alberto Landero Figueroa, Pavlos Zarmpas, Cristina Cunha, Tonia Akoumianaki, Kostas Stylianou, George S. Deepe, George Samonis, João F. Lacerda, António Campos, Dimitrios P. Kontoyiannis, Nikolaos Mihalopoulos, Kyung J. Kwon-Chung, Jamel El-Benna, Isabel Valsecchi, Anne Beauvais, Axel A. Brakhage, Nuno M. NevesJean Paul Latge, Georgios Chamilos

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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 Ca 2+ signalling pathway that depends on intracellular Ca 2+ sources from endoplasmic reticulum, endoplasmic reticulum-phagosome communication, Ca 2+ 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 Ca 2+ -CaM signalling in aspergillosis. Finally, we demonstrate that Ca 2+ sequestration by Aspergillus melanin inside the phagosome abrogates activation of Ca 2+ -CaM signalling to inhibit LAP. These findings reveal the important role of Ca 2+ -CaM signalling in antifungal immunity and identify an immunological function of Ca 2+ binding by melanin pigments with broad physiological implications beyond fungal disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)791-803
Number of pages13
JournalNature microbiology
Volume3
Issue number7
DOIs
StatePublished - Jul 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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