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

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.

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 Creators:
Kurz, Angela R. M.1, Author
Pruenster, Monika1, Author
Rohwedder, Ina1, Author
Ramadass, Mahalakshmi1, Author
Schaefer, Kerstin1, Author
Harrison, Ute1, Author
Gouveia, Gabriel1, Author
Nussbaum, Claudia1, Author
Immler, Roland1, Author
Wiessner, Johannes R.1, Author
Margraf, Andreas1, Author
Lim, Dae-Sik1, Author
Walzog, Barbara1, Author
Dietzel, Steffen1, Author
Moser, Markus2, Author              
Klein, Christoph1, Author
Vestweber, Dietmar1, Author
Haas, Rainer1, Author
Catz, Sergio D.1, Author
Sperandio, Markus1, Author
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1external, ou_persistent22              
2Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              

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Free keywords: IN-VIVO; LEUKOCYTE MIGRATION; TRANSENDOTHELIAL MIGRATION; LYMPHOCYTE TRAFFICKING; EXTRACELLULAR-MATRIX; ACTIVATING PROTEIN; GRANULE SECRETION; CELL RECRUITMENT; LAMININ ISOFORMS; NADPH OXIDASEResearch & Experimental Medicine;
 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.

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Language(s): eng - English
 Dates: 2016-10-042016-11-01
 Publication Status: Published in print
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000386992900009
DOI: 10.1172/JCI87043
 Degree: -

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Title: The Journal of Clinical Investigation
Source Genre: Journal
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Publ. Info: New York, NY : American Society for Clinical Investigation
Pages: - Volume / Issue: 126 (11) Sequence Number: - Start / End Page: 4125 - 4139 Identifier: ISSN: 0021-9738
CoNE: https://pure.mpg.de/cone/journals/resource/954926940717_2