Calcium sequestration by fungal melanin inhibits calcium–calmodulin signalling to prevent LC3-associated phagocytosis
Irene Kyrmizi
(1, 2)
,
Helena Ferreira
(3, 4)
,
Agostinho Carvalho
(4, 5)
,
Julio Alberto Landero Figueroa
(6, 7)
,
Pavlos Zarmpas
(1)
,
Cristina Cunha
(4, 5)
,
Tonia Akoumianaki
(1)
,
Kostas Stylianou
(8)
,
George Deepe
(9)
,
George Samonis
(1)
,
João Lacerda
(10, 11)
,
Antonio Campos
(12)
,
Dimitrios Kontoyiannis
(13)
,
Nikolaos Mihalopoulos
(1)
,
Kyung Kwon-Chung
(14)
,
Jamel El-Benna
(15, 16)
,
Isabel Valsecchi
(17)
,
Anne Beauvais
(17)
,
Axel Brakhage
(18)
,
Nuno M. Neves
(3, 4)
,
Jean-Paul Latge
(17)
,
Georgios Chamilos
(1, 2)
1
UOC -
University of Crete [Heraklion]
2 IMBB-FORTH - Institute of Molecular Biology and Biotechnology
3 3B’s Research Group - Biomaterials, Biodegradables and Biomimetics [Guimarães]
4 ICVS/3B's—PT Government Associate Laboratory [Braga, Portugal]
5 ICVS - Life and Health Sciences Research Institute [Braga]
6 Agilent Technologies Metallomics Center of the Americas [Cincinnati]
7 Department of Chemistry [Cincinnati]
8 Cyprus University of Technology
9 Division of Infectious Diseases [Cincinnati, OH, États-Unis]
10 iMM - Instituto de Medicina Molecular
11 Hospital de Santa Maria [Lisboa]
12 IPO Porto - Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto
13 Department of Infectious Diseases [Austin]
14 LCIM - Laboratory of Clinical Immunology and Microbiology [Bethesda, MA, USA]
15 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
16 CRB3 - Centre de recherche biomédicale Bichat-Beaujon
17 Aspergillus
18 Department of Molecular and Applied Microbiology [Jena]
2 IMBB-FORTH - Institute of Molecular Biology and Biotechnology
3 3B’s Research Group - Biomaterials, Biodegradables and Biomimetics [Guimarães]
4 ICVS/3B's—PT Government Associate Laboratory [Braga, Portugal]
5 ICVS - Life and Health Sciences Research Institute [Braga]
6 Agilent Technologies Metallomics Center of the Americas [Cincinnati]
7 Department of Chemistry [Cincinnati]
8 Cyprus University of Technology
9 Division of Infectious Diseases [Cincinnati, OH, États-Unis]
10 iMM - Instituto de Medicina Molecular
11 Hospital de Santa Maria [Lisboa]
12 IPO Porto - Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto
13 Department of Infectious Diseases [Austin]
14 LCIM - Laboratory of Clinical Immunology and Microbiology [Bethesda, MA, USA]
15 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
16 CRB3 - Centre de recherche biomédicale Bichat-Beaujon
17 Aspergillus
18 Department of Molecular and Applied Microbiology [Jena]
Jamel El-Benna
- Fonction : Auteur
- PersonId : 739956
- IdHAL : jamel-el-benna
- ORCID : 0000-0001-5733-216X
- IdRef : 130373249
Résumé
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.