title: Fungal recognition enhances mannose receptor shedding through dectin-1 engagement.
abstract: The mannose receptor (MR) is an endocytic type I membrane molecule with a broad ligand specificity that is involved in both hemostasis and pathogen recognition. Membrane-anchored MR is cleaved by a metalloproteinase into functional soluble MR (sMR) composed of the extracellular domains of intact MR. Although sMR production was initially considered a constitutive process, enhanced MR shedding has been observed in response to the fungal pathogen Pneumocystis carinii. In this work, we have investigated the mechanism mediating enhanced MR shedding in response to fungi. We show that other fungal species, including Candida albicans and Aspergillus fumigatus, together with zymosan, a preparation of the cell wall of Saccharomyces cerevisiae, mimic the effect of P. carinii on sMR production and that this effect takes place mainly through β-glucan recognition. Additionally, we demonstrate that MR cleavage in response to C. albicans and bioactive particulate β-glucan requires expression of dectin-1. Our data, obtained using specific inhibitors, are consistent with the canonical Syk-mediated pathway triggered by dectin-1 being mainly responsible for inducing MR shedding, with Raf-1 being partially involved. As in the case of steady-state conditions, MR shedding in response to C. albicans and β-glucan particles requires metalloprotease activity. The induction of MR shedding by dectin-1 has clear implications for the role of MR in fungal recognition, as sMR was previously shown to retain the ability to bind fungal pathogens and can interact with numerous host molecules, including lysosomal hydrolases. Thus, MR cleavage could also impact on the magnitude of inflammation during fungal infection.
authors.affiliation: From the School of Molecular Medical Sciences,; Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
authors.forename: Umut
authors.initials: U
authors.lastname: Gazi
authors.affiliation: the Department of Infection, Immunity, and Biochemistry, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
authors.forename: Marcela
authors.initials: M
authors.lastname: Rosas
authors.affiliation: From the School of Molecular Medical Sciences,; Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
authors.forename: Sonali
authors.initials: S
authors.lastname: Singh
authors.affiliation: the Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Heinsbroek
authors.affiliation: Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom,; Division of Therapeutics and Molecular Medicine, and.
authors.forename: Imran
authors.initials: I
authors.lastname: Haq
authors.affiliation: Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom,; Division of Therapeutics and Molecular Medicine, and.
authors.forename: Simon
authors.initials: S
authors.lastname: Johnson
authors.affiliation: the Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB24 3FX, Scotland, United Kingdom, and.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: the Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.affiliation: the Department of Infection, Immunity, and Biochemistry, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.affiliation: From the School of Molecular Medical Sciences,; Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom,. Electronic address: luisa.martinez-pomares@nottingham.ac.uk.
authors.forename: Luisa
authors.initials: L
authors.lastname: Martinez-Pomares
mesh_terms: D000818:Animals; D005658:Fungi / Q000276:immunology / Q000378:metabolism*; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009181:Mycoses / Q000276:immunology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D000099181:Dectin-1