Fungal recognition enhances mannose receptor shedding through dectin-1 engagement

Umut Gazi, Marcela Rosas, Sonali Singh, Sigrid Heinsbroek, Imran Haq, Simon Johnson, Gordon D Brown, David L Williams, Philip R Taylor, Luisa Martinez-Pomares

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 ß-glucan recognition. Additionally, we demonstrate that MR cleavage in response to C. albicans and bioactive particulate ß-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 ß-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.
Original languageEnglish
Pages (from-to)7822-7829
Number of pages8
JournalThe Journal of Biological Chemistry
Volume286
Issue number10
Early online date4 Mar 2011
DOIs
Publication statusPublished - 11 Mar 2011

Fingerprint

Glucans
Pathogens
Candida albicans
Pneumocystis carinii
Metalloproteases
dectin 1
mannose receptor
Membranes
Molecules
Zymosan
Aspergillus fumigatus
Mycoses
Candida
Aspergillus
Hydrolases
Hemostasis
Fungi
Yeast
Cell Wall
Saccharomyces cerevisiae

Keywords

  • animals
  • fungi
  • lectins, C-type
  • macrophages, peritoneal
  • mannose-binding lectins
  • membrane proteins
  • mice
  • mice, inbred BALB C
  • mycoses
  • nerve tissue proteins
  • receptors, cell surface
  • ADAM
  • ADAMTS
  • macrophage
  • inflammation
  • lectin
  • metalloprotease
  • mouse
  • shedding

Cite this

Gazi, U., Rosas, M., Singh, S., Heinsbroek, S., Haq, I., Johnson, S., ... Martinez-Pomares, L. (2011). Fungal recognition enhances mannose receptor shedding through dectin-1 engagement. The Journal of Biological Chemistry, 286(10), 7822-7829. https://doi.org/10.1074/jbc.M110.185025

Fungal recognition enhances mannose receptor shedding through dectin-1 engagement. / Gazi, Umut; Rosas, Marcela; Singh, Sonali; Heinsbroek, Sigrid; Haq, Imran; Johnson, Simon; Brown, Gordon D; Williams, David L; Taylor, Philip R; Martinez-Pomares, Luisa.

In: The Journal of Biological Chemistry, Vol. 286, No. 10, 11.03.2011, p. 7822-7829.

Research output: Contribution to journalArticle

Gazi, U, Rosas, M, Singh, S, Heinsbroek, S, Haq, I, Johnson, S, Brown, GD, Williams, DL, Taylor, PR & Martinez-Pomares, L 2011, 'Fungal recognition enhances mannose receptor shedding through dectin-1 engagement', The Journal of Biological Chemistry, vol. 286, no. 10, pp. 7822-7829. https://doi.org/10.1074/jbc.M110.185025
Gazi, Umut ; Rosas, Marcela ; Singh, Sonali ; Heinsbroek, Sigrid ; Haq, Imran ; Johnson, Simon ; Brown, Gordon D ; Williams, David L ; Taylor, Philip R ; Martinez-Pomares, Luisa. / Fungal recognition enhances mannose receptor shedding through dectin-1 engagement. In: The Journal of Biological Chemistry. 2011 ; Vol. 286, No. 10. pp. 7822-7829.
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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 {\ss}-glucan recognition. Additionally, we demonstrate that MR cleavage in response to C. albicans and bioactive particulate {\ss}-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 {\ss}-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.",
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