title: SHIP-1 Couples to the Dectin-1 hemITAM and Selectively Modulates Reactive Oxygen Species Production in Dendritic Cells in Response to Candida albicans.
abstract: Dectin-1 (Clec7a) is a paradigmatic C-type lectin receptor that binds Syk through a hemITAM motif and couples sensing of pathogens such as fungi to induction of innate responses. Dectin-1 engagement triggers a plethora of activating events, but little is known about the modulation of such pathways. Trying to define a more precise picture of early Dectin-1 signaling, we explored the interactome of the intracellular tail of the receptor in mouse dendritic cells. We found unexpected binding of SHIP-1 phosphatase to the phosphorylated hemITAM. SHIP-1 colocalized with Dectin-1 during phagocytosis of zymosan in a hemITAM-dependent fashion. Moreover, endogenous SHIP-1 relocated to live or heat-killed Candida albicans-containing phagosomes in a Dectin-1-dependent manner in GM-CSF-derived bone marrow cells (GM-BM). However, SHIP-1 absence in GM-BM did not affect activation of MAPK or production of cytokines and readouts dependent on NF-κB and NFAT. Notably, ROS production was enhanced in SHIP-1-deficient GM-BM treated with heat-killed C. albicans, live C. albicans, or the specific Dectin-1 agonists curdlan or whole glucan particles. This increased oxidative burst was dependent on Dectin-1, Syk, PI3K, phosphoinositide-dependent protein kinase 1, and NADPH oxidase. GM-BM from CD11c∆SHIP-1 mice also showed increased killing activity against live C. albicans that was dependent on Dectin-1, Syk, and NADPH oxidase. These results illustrate the complexity of myeloid C-type lectin receptor signaling, and how an activating hemITAM can also couple to intracellular inositol phosphatases to modulate selected functional responses and tightly regulate processes such as ROS production that could be deleterious to the host.
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Blanco-Menéndez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Del Fresno
authors.affiliation: Microbiology and Immunology Department, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Fernandes
authors.affiliation: Proteomic Unit, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Conde-Garrosa
authors.affiliation: Microbiology and Immunology Department, SUNY Upstate Medical University, Syracuse, New York, USA.|Pediatrics Department, SUNY Upstate Medical University, Syracuse, New York, USA.|Chemistry Department, Syracuse University, Syracuse, New York, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Kerr
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sancho
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002176:Candida albicans / Q000276:immunology* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000099181:Dectin-1
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000072181:Inositol Polyphosphate 5-Phosphatases; D037181:Lectins, C-Type; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D017382:Reactive Oxygen Species; D000099181:Dectin-1; C000606433:Inpp5d protein, mouse