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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents



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ID: 732134.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane
Authors:Kurz, A. R.; Pruenster, M.; Rohwedder, I.; Ramadass, M.; Schafer, K.; Harrison, U.; Gouveia, G.; Nussbaum, C.; Immler, R.; Wiessner, J. R.; Margraf, A.; Lim, D. S.; Walzog, B.; Dietzel, S.; Moser, M.; Klein, C.; Vestweber, D.; Haas, R.; Catz, S. D.; Sperandio, M.
Date of Publication (YYYY-MM-DD):2016-11-01
Title of Journal:J Clin Invest
Volume:126
Issue / Number:11
Start Page:4125
End Page:4139
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
Identifiers:ISSN:1558-8238 (Electronic) 0021-9738 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/27701149 [ID No:2]
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