title: MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane.
abstract: 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.
authors.forename: Angela R M
authors.initials: AR
authors.lastname: Kurz
authors.forename: Monika
authors.initials: M
authors.lastname: Pruenster
authors.forename: Ina
authors.initials: I
authors.lastname: Rohwedder
authors.forename: Mahalakshmi
authors.initials: M
authors.lastname: Ramadass
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schäfer
authors.forename: Ute
authors.initials: U
authors.lastname: Harrison
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gouveia
authors.forename: Claudia
authors.initials: C
authors.lastname: Nussbaum
authors.forename: Roland
authors.initials: R
authors.lastname: Immler
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Wiessner
authors.forename: Andreas
authors.initials: A
authors.lastname: Margraf
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Barbara
authors.initials: B
authors.lastname: Walzog
authors.forename: Steffen
authors.initials: S
authors.lastname: Dietzel
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Catz
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
mesh_terms: D000009:Abdominal Muscles / Q000098:blood supply / Q000276:immunology; D000818:Animals; D001485:Basement Membrane / Q000276:immunology; D001693:Biological Transport, Active / Q000235:genetics / Q000276:immunology; D005753:Gastric Mucosa / Q000737:chemistry / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000276:immunology; D039121:Integrin alpha6beta1 / Q000235:genetics / Q000276:immunology; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D022142:Secretory Vesicles / Q000235:genetics / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics / Q000276:immunology*; D014699:Venules / Q000276:immunology; D033921:Vesicular Transport Proteins
chemical_list: D039201:Integrin alpha3beta1; D039121:Integrin alpha6beta1; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C424133:Sytl1 protein, mouse; D033921:Vesicular Transport Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D019272:Leukocyte Elastase