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Journal Article

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

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Moser,  Markus
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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JCI87043.pdf
(Publisher version), 4MB

Supplementary Material (public)

JCI87043.sd.pdf
(Supplementary material), 398KB

Citation

Kurz, A. R. M., Pruenster, M., Rohwedder, I., Ramadass, M., Schaefer, K., Harrison, U., et al. (2016). MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane. The Journal of Clinical Investigation, 126(11), 4125-4139. doi:10.1172/JCI87043.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-18DB-E
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.