title: Dectin-1 activation controls maturation of β-1,3-glucan-containing phagosomes.
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.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Mansour
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Tam
authors.forename: Nida S
authors.initials: NS
authors.lastname: Khan
authors.forename: Michael
authors.initials: M
authors.lastname: Seward
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Davids
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Puranam
authors.forename: Anna
authors.initials: A
authors.lastname: Sokolovska
authors.forename: David B
authors.initials: DB
authors.lastname: Sykes
authors.forename: Zeina
authors.initials: Z
authors.lastname: Dagher
authors.forename: Christine
authors.initials: C
authors.lastname: Becker
authors.forename: Antoine
authors.initials: A
authors.lastname: Tanne
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Reedy
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Stuart
authors.forename: Jatin M
authors.initials: JM
authors.lastname: Vyas
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000072377:Syk Kinase; D047071:beta-Glucans / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D047071:beta-Glucans; D020696:rab5 GTP-Binding Proteins; D000099181:Dectin-1; C033363:beta-1,3-glucan; C000606897:Syk protein, mouse
keywords: Acidification; Dectin-1; Lysosomes; Macrophages; Pathogen-associated Molecular Pattern (PAMP); Pattern Recognition Receptor; Phagocytosis; Phagosome; Syk; β-1,3-Glucan