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Munc13-4 restricts motility of rab27a-expressing vesicles to facilitate lipopolysaccharide-induced priming of exocytosis in neutrophils

Academic Article
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Overview

authors

  • Johnson, J. L.
  • Hong, H.
  • Monfregola, J.
  • Kiosses, W. B.
  • Catz, Sergio

publication date

  • February 2011

journal

  • Journal of Biological Chemistry  Journal

abstract

  • LPS is an efficient sensitizer of the neutrophil exocytic response to a second stimulus. Although neutrophil exocytosis in response to pathogen-derived molecules plays an important role in the innate immune response to infections, the molecular mechanism underlying LPS-dependent regulation of neutrophil exocytosis is currently unknown. The small GTPase Rab27a and its effector Munc13-4 regulate exocytosis in hematopoietic cells. Whether Rab27a and Munc13-4 modulate discrete steps or the same steps during exocytosis also remains unknown. Here, using Munc13-4- and Rab27a-deficient neutrophils, we analyzed the mechanism of lipopolysaccharide-dependent vesicular priming to amplify exocytosis of azurophilic granules. We found that both Munc13-4 and Rab27a are necessary to mediate LPS-dependent priming of exocytosis. However, we show that LPS-induced mobilization of a small population of readily releasable vesicles is a Munc13-4-dependent but Rab27a-independent process. LPS-induced priming regulation could not be fully explained by secretory organelle maturation as the redistribution of the secretory proteins Rab27a or Munc13-4 in response to LPS treatment was minimal. Using total internal reflection fluorescence microscopy and a novel mouse model expressing EGFP-Rab27a under the endogenous Rab27a promoter but lacking Munc13-4, we demonstrate that Munc13-4 is essential for the mechanism of LPS-dependent exocytosis in neutrophils and unraveled a novel mechanism of vesicular dynamics in which Munc13-4 restricts motility of Rab27a-expressing vesicles to facilitate lipopolysaccharide-induced priming of exocytosis.

subject areas

  • Animals
  • Exocytosis
  • Gene Expression Regulation
  • Lipopolysaccharides
  • Membrane Proteins
  • Mice
  • Mice, Mutant Strains
  • Neutrophils
  • Secretory Vesicles
  • rab GTP-Binding Proteins
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Identity

PubMed Central ID

  • PMC3037678

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M110.184762

PubMed ID

  • 21148308
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Additional Document Info

start page

  • 5647

end page

  • 5656

volume

  • 286

issue

  • 7

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