MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane

J Clin Invest. 2016 Nov 1;126(11):4125-4139. doi: 10.1172/JCI87043. Epub 2016 Oct 4.


Neutrophils need to penetrate the perivascular basement membrane for successful extravasation into inflamed tissue, but this process is incompletely understood. Recent findings have associated mammalian sterile 20-like kinase 1 (MST1) loss of function with a human primary immunodeficiency disorder, suggesting that MST1 may be involved in immune cell migration. Here, we have shown that MST1 is a critical regulator of neutrophil extravasation during inflammation. Mst1-deficient (Mst1-/-) neutrophils were unable to migrate into inflamed murine cremaster muscle venules, instead persisting between the endothelium and the basement membrane. Mst1-/- neutrophils also failed to extravasate from gastric submucosal vessels in a murine model of Helicobacter pylori infection. Mechanistically, we observed defective translocation of VLA-3, VLA-6, and neutrophil elastase from intracellular vesicles to the surface of Mst1-/- neutrophils, indicating that MST1 is required for this crucial step in neutrophil transmigration. Furthermore, we found that MST1 associates with the Rab27 effector protein synaptotagmin-like protein 1 (JFC1, encoded by Sytl1 in mice), but not Munc13-4, thereby regulating the trafficking of Rab27-positive vesicles to the cellular membrane. Together, these findings highlight a role for MST1 in vesicle trafficking and extravasation in neutrophils, providing an additional mechanistic explanation for the severe immune defect observed in patients with MST1 deficiency.

MeSH terms

  • Abdominal Muscles / blood supply
  • Abdominal Muscles / immunology
  • Animals
  • Basement Membrane / immunology
  • Biological Transport, Active / genetics
  • Biological Transport, Active / immunology
  • Gastric Mucosa / chemistry
  • Gastric Mucosa / immunology
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / immunology*
  • Humans
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology
  • Integrin alpha3beta1 / genetics
  • Integrin alpha3beta1 / immunology
  • Integrin alpha6beta1 / genetics
  • Integrin alpha6beta1 / immunology
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Knockout
  • Neutrophils / immunology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology*
  • Secretory Vesicles / genetics
  • Secretory Vesicles / immunology*
  • Transendothelial and Transepithelial Migration / genetics
  • Transendothelial and Transepithelial Migration / immunology*
  • Venules / immunology
  • Vesicular Transport Proteins


  • Integrin alpha3beta1
  • Integrin alpha6beta1
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Sytl1 protein, mouse
  • Vesicular Transport Proteins
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • Leukocyte Elastase

Supplementary concepts

  • Immune Deficiency Disease