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J Biol Chem. 2013 May 31;288(22):16043-54. doi: 10.1074/jbc.M113.473223. Epub 2013 Apr 22.

Dectin-1 activation controls maturation of β-1,3-glucan-containing phagosomes.

Author information

1
Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Abstract

Elimination of fungal pathogens by phagocytes requires phagosome maturation, a process that involves the recruitment and fusion of intracellular proteins. The role of Dectin-1, a β-1,3-glucan receptor, critical for fungal recognition and triggering of Th17 responses, to phagosomal maturation has not been defined. We show that GFP-Dectin-1 translocates to the fungal phagosome, but its signal decays after 2 h. Inhibition of acidification results in retention of GFP-Dectin-1 to phagosome membranes highlighting the requirement for an acidic pH. Following β-1,3-glucan recognition, GFP-Dectin-1 undergoes tyrosine phosphorylation by Src kinases with subsequent Syk activation. Our results demonstrate that Syk is activated independently of intraphagosomal pH. Inhibition of Src or Syk results in prolonged retention of GFP-Dectin-1 to the phagosome signifying a link between Syk and intraphagosomal pH. β-1,3-glucan phagosomes expressing a signaling incompetent Dectin-1 failed to mature as demonstrated by prolonged Dectin-1 retention, presence of Rab5B, failure to acquire LAMP-1 and inability to acidify. Phagosomes containing Candida albicans also require Dectin-1-dependent Syk activation for phagosomal maturation. Taken together, these results support a model where Dectin-1 not only controls internalization of β-1,3-glucan containing cargo and triggers proinflammatory cytokines, but also acts as a master regulator for subsequent phagolysosomal maturation through Syk activation.

KEYWORDS:

Acidification; Dectin-1; Lysosomes; Macrophages; Pathogen-associated Molecular Pattern (PAMP); Pattern Recognition Receptor; Phagocytosis; Phagosome; Syk; β-1,3-Glucan

PMID:
23609446
PMCID:
PMC3668760
DOI:
10.1074/jbc.M113.473223
[Indexed for MEDLINE]
Free PMC Article

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