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  1. Artikel ; Online: Double-Hit-Induced Leukocyte Extravasation Driven by Endothelial Adherens Junction Destabilization.

    Morsing, Sofia K H / Al-Mardini, Claudia / van Stalborch, Anne-Marieke D / Schillemans, Maaike / Bierings, Ruben / Vlaar, Alexander P / van Buul, Jaap D

    Journal of immunology (Baltimore, Md. : 1950)

    2020  Band 205, Heft 2, Seite(n) 511–520

    Abstract: During inflammation, endothelial cells are bombarded with cytokines and other stimuli from surrounding cells. Leukocyte extravasation and vascular leakage are both prominent but believed to be uncoupled as they occur in separate spatiotemporal patterns. ... ...

    Abstract During inflammation, endothelial cells are bombarded with cytokines and other stimuli from surrounding cells. Leukocyte extravasation and vascular leakage are both prominent but believed to be uncoupled as they occur in separate spatiotemporal patterns. In this study, we investigated a "double-hit" approach on primary human endothelial cells primed with LPS followed by histamine. Using neutrophil transendothelial migration (TEM) under physiological flow assays, we found that an LPS-primed endothelium synergistically enhanced neutrophil TEM when additionally treated with histamine, whereas the effects on neutrophil TEM of the individual stimuli were moderate to undetectable. Interestingly, the double-hit-induced TEM increase was not due to decreased endothelial barrier, increased adhesion molecule expression, or Weibel-Palade body release. Instead, we found that it was directly correlated with junctional remodeling. Compounds that increased junctional "linearity" (i.e., stability) counteracted the double-hit effect on neutrophil TEM. We conclude that a compound, in this case histamine (which has a short primary effect on vascular permeability), can have severe secondary effects on neutrophil TEM in combination with an inflammatory stimulus. This effect is due to synergic modifications of the endothelial cytoskeleton and junctional remodeling. Therefore, we hypothesize that junctional linearity is a better and more predictive readout than endothelial resistance for compounds aiming to attenuate inflammation.
    Mesh-Begriff(e) Adherens Junctions/metabolism ; Capillary Permeability ; Cell Adhesion ; Cell Adhesion Molecules/metabolism ; Cell Movement ; Cells, Cultured ; Cytokines/metabolism ; Cytoskeleton/metabolism ; Endothelium, Vascular/physiology ; Histamine/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Inflammation/pathology ; Leukocytes/physiology ; Lipopolysaccharides/metabolism ; Neutrophils/physiology ; Transendothelial and Transepithelial Migration
    Chemische Substanzen Cell Adhesion Molecules ; Cytokines ; Lipopolysaccharides ; Histamine (820484N8I3)
    Sprache Englisch
    Erscheinungsdatum 2020-06-12
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1900816
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: Interaction networks of Weibel-Palade body regulators syntaxin-3 and syntaxin binding protein 5 in endothelial cells

    Schillemans, Maaike / Karampini, Ellie / Hoogendijk, Arie J / Wahedi, Maryam / van Alphen, Floris P.J / van den Biggelaar, Maartje / Voorberg, Jan / Bierings, Ruben

    Journal of proteomics. 2019 Aug. 15, v. 205

    2019  

    Abstract: The endothelium stores the hemostatic protein Von Willebrand factor (VWF) in endothelial storage organelles called Weibel-Palade bodies (WPBs). During maturation, WPBs recruit a complex of Rab GTPases and effectors that associate with components of the ... ...

    Abstract The endothelium stores the hemostatic protein Von Willebrand factor (VWF) in endothelial storage organelles called Weibel-Palade bodies (WPBs). During maturation, WPBs recruit a complex of Rab GTPases and effectors that associate with components of the SNARE machinery that control WPB exocytosis. Recent genome wide association studies have found links between genetic variations in the SNAREs syntaxin-2 (STX2) and syntaxin binding protein 5 (STXBP5) and VWF plasma levels, suggesting a role for SNARE proteins in regulating VWF release. Moreover, we have previously identified the SNARE proteins syntaxin-3 and STXBP1 as regulators of WPB release. In this study we used an unbiased iterative interactomic approach to identify new components of the WPB exocytotic machinery. An interactome screen of syntaxin-3 identifies a number of SNAREs and SNARE associated proteins (STXBP2, STXBP5, SNAP23, NAPA and NSF). We show that the VAMP-like domain (VLD) of STXBP5 is indispensable for the interaction with SNARE proteins and this capacity of the VLD could be exploited to identify an extended set of novel endothelial SNARE interactors of STXBP5. In addition, an STXBP5 variant with an N436S substitution, which is linked to lower VWF plasma levels, does not show a difference in interactome when compared with WT STXBP5.The hemostatic protein Von Willebrand factor plays a pivotal role in vascular health: quantitative or qualitative deficiencies of VWF can lead to bleeding, while elevated levels of VWF are associated with increased risk of thrombosis. Tight regulation of VWF secretion from WPBs is therefore essential to maintain vascular homeostasis. We used an unbiased proteomic screen to identify new components of the regulatory machinery that controls WPB exocytosis. Our data expand the endothelial SNARE protein network and provide a set of novel candidate WPB regulators that may contribute to regulation of VWF plasma levels and vascular health.
    Schlagwörter SNARE proteins ; binding proteins ; blood coagulation factors ; endothelial cells ; endothelium ; exocytosis ; genetic variation ; genome-wide association study ; guanosinetriphosphatase ; hemorrhage ; homeostasis ; organelles ; proteomics ; risk ; secretion ; thrombosis
    Sprache Englisch
    Erscheinungsverlauf 2019-0815
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel
    ZDB-ID 2400835-7
    ISSN 1876-7737 ; 1874-3919
    ISSN (online) 1876-7737
    ISSN 1874-3919
    DOI 10.1016/j.jprot.2019.103417
    Datenquelle NAL Katalog (AGRICOLA)

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  3. Artikel ; Online: Comparing autotransporter β-domain configurations for their capacity to secrete heterologous proteins to the cell surface.

    Jong, Wouter S P / Schillemans, Maaike / Ten Hagen-Jongman, Corinne M / Luirink, Joen / van Ulsen, Peter

    PloS one

    2018  Band 13, Heft 2, Seite(n) e0191622

    Abstract: Monomeric autotransporters have been extensively used for export of recombinant proteins to the cell surface of Gram-negative bacteria. A bottleneck in the biosynthesis of such constructs is the passage of the outer membrane, which is facilitated by the ... ...

    Abstract Monomeric autotransporters have been extensively used for export of recombinant proteins to the cell surface of Gram-negative bacteria. A bottleneck in the biosynthesis of such constructs is the passage of the outer membrane, which is facilitated by the β-domain at the C terminus of an autotransporter in conjunction with the Bam complex in the outer membrane. We have evaluated eight β-domain constructs for their capacity to secrete fused proteins to the cell surface. These constructs derive from the monomeric autotransporters Hbp, IgA protease, Ag43 and EstA and the trimeric autotransporter Hia, which all were selected because they have been previously used for secretion of recombinant proteins. We fused three different protein domains to the eight β-domain constructs, being a Myc-tag, the Hbp passenger and a nanobody or VHH domain, and assessed expression, membrane insertion and surface exposure. Our results show that expression levels differed considerably between the constructs tested. The constructs that included the β-domains of Hbp and IgA protease appeared the most efficient and resulted in expression levels that were detectable on Coomassie-stained SDS-PAGE gels. The VHH domain appeared the most difficult fusion partner to export, probably due to its complex immunoglobulin-like structure with a tertiary structure stabilized by an intramolecular disulfide bond. Overall, the Hbp β-domain compared favorably in exporting the fused recombinant proteins, because it showed in every instance tested a good level of expression, stable membrane insertion and clear surface exposure.
    Mesh-Begriff(e) Cell Membrane/metabolism ; Escherichia coli/metabolism ; Escherichia coli Proteins/metabolism ; Membrane Transport Proteins/metabolism
    Chemische Substanzen Escherichia coli Proteins ; Membrane Transport Proteins
    Sprache Englisch
    Erscheinungsdatum 2018
    Erscheinungsland United States
    Dokumenttyp Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0191622
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Defective AP-3-dependent VAMP8 trafficking impairs Weibel-Palade body exocytosis in Hermansky-Pudlak Syndrome type 2 blood outgrowth endothelial cells.

    Karampini, Ellie / Schillemans, Maaike / Hofman, Menno / van Alphen, Floris / de Boer, Martin / Kuijpers, Taco W / van den Biggelaar, Maartje / Voorberg, Jan / Bierings, Ruben

    Haematologica

    2019  Band 104, Heft 10, Seite(n) 2091–2099

    Abstract: Weibel-Palade bodies are endothelial secretory organelles that contain von Willebrand factor, P-selectin and CD63. Release of von Willebrand factor from Weibel-Palade bodies is crucial for platelet adhesion during primary hemostasis. Endosomal ... ...

    Abstract Weibel-Palade bodies are endothelial secretory organelles that contain von Willebrand factor, P-selectin and CD63. Release of von Willebrand factor from Weibel-Palade bodies is crucial for platelet adhesion during primary hemostasis. Endosomal trafficking of proteins like CD63 to Weibel-Palade bodies during maturation is dependent on the adaptor protein complex 3 complex. Mutations in the
    Mesh-Begriff(e) Adaptor Protein Complex 3/genetics ; Adaptor Protein Complex 3/metabolism ; Adaptor Protein Complex beta Subunits/genetics ; Adaptor Protein Complex beta Subunits/metabolism ; Calcium Signaling ; Cells, Cultured ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Exocytosis ; Hermanski-Pudlak Syndrome/genetics ; Hermanski-Pudlak Syndrome/metabolism ; Hermanski-Pudlak Syndrome/pathology ; Humans ; Mutation ; Protein Transport ; R-SNARE Proteins/genetics ; R-SNARE Proteins/metabolism ; Weibel-Palade Bodies/genetics ; Weibel-Palade Bodies/metabolism ; Weibel-Palade Bodies/pathology
    Chemische Substanzen AP3B1 protein, human ; Adaptor Protein Complex 3 ; Adaptor Protein Complex beta Subunits ; R-SNARE Proteins ; VAMP8 protein, human
    Sprache Englisch
    Erscheinungsdatum 2019-01-10
    Erscheinungsland Italy
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2018.207787
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Alternative trafficking of Weibel-Palade body proteins in CRISPR/Cas9-engineered von Willebrand factor-deficient blood outgrowth endothelial cells.

    Schillemans, Maaike / Kat, Marije / Westeneng, Jurjen / Gangaev, Anastasia / Hofman, Menno / Nota, Benjamin / van Alphen, Floris P J / de Boer, Martin / van den Biggelaar, Maartje / Margadant, Coert / Voorberg, Jan / Bierings, Ruben

    Research and practice in thrombosis and haemostasis

    2019  Band 3, Heft 4, Seite(n) 718–732

    Abstract: Background: Synthesis of the hemostatic protein von Willebrand factor (VWF) drives formation of endothelial storage organelles called Weibel-Palade bodies (WPBs). In the absence of VWF, angiogenic and inflammatory mediators that are costored in WPBs are ...

    Abstract Background: Synthesis of the hemostatic protein von Willebrand factor (VWF) drives formation of endothelial storage organelles called Weibel-Palade bodies (WPBs). In the absence of VWF, angiogenic and inflammatory mediators that are costored in WPBs are subject to alternative trafficking routes. In patients with von Willebrand disease (VWD), partial or complete absence of VWF/WPBs may lead to additional bleeding complications, such as angiodysplasia. Studies addressing the role of VWF using VWD patient-derived blood outgrowth endothelial cells (BOECs) have reported conflicting results due to the intrinsic heterogeneity of patient-derived BOECs.
    Objective: To generate a VWF-deficient endothelial cell model using clustered regularly interspaced short palindromic repeats (CRISPR) genome engineering of blood outgrowth endothelial cells.
    Methods: We used CRISPR/CRISPR-associated protein 9 editing in single-donor cord blood-derived BOECs (cbBOECs) to generate clonal
    Results: Two
    Conclusions: CRISPR editing of
    Sprache Englisch
    Erscheinungsdatum 2019-08-01
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 2475-0379
    ISSN (online) 2475-0379
    DOI 10.1002/rth2.12242
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Interaction networks of Weibel-Palade body regulators syntaxin-3 and syntaxin binding protein 5 in endothelial cells.

    Schillemans, Maaike / Karampini, Ellie / Hoogendijk, Arie J / Wahedi, Maryam / van Alphen, Floris P J / van den Biggelaar, Maartje / Voorberg, Jan / Bierings, Ruben

    Journal of proteomics

    2019  Band 205, Seite(n) 103417

    Abstract: The endothelium stores the hemostatic protein Von Willebrand factor (VWF) in endothelial storage organelles called Weibel-Palade bodies (WPBs). During maturation, WPBs recruit a complex of Rab GTPases and effectors that associate with components of the ... ...

    Abstract The endothelium stores the hemostatic protein Von Willebrand factor (VWF) in endothelial storage organelles called Weibel-Palade bodies (WPBs). During maturation, WPBs recruit a complex of Rab GTPases and effectors that associate with components of the SNARE machinery that control WPB exocytosis. Recent genome wide association studies have found links between genetic variations in the SNAREs syntaxin-2 (STX2) and syntaxin binding protein 5 (STXBP5) and VWF plasma levels, suggesting a role for SNARE proteins in regulating VWF release. Moreover, we have previously identified the SNARE proteins syntaxin-3 and STXBP1 as regulators of WPB release. In this study we used an unbiased iterative interactomic approach to identify new components of the WPB exocytotic machinery. An interactome screen of syntaxin-3 identifies a number of SNAREs and SNARE associated proteins (STXBP2, STXBP5, SNAP23, NAPA and NSF). We show that the VAMP-like domain (VLD) of STXBP5 is indispensable for the interaction with SNARE proteins and this capacity of the VLD could be exploited to identify an extended set of novel endothelial SNARE interactors of STXBP5. In addition, an STXBP5 variant with an N436S substitution, which is linked to lower VWF plasma levels, does not show a difference in interactome when compared with WT STXBP5. SIGNIFICANCE: The hemostatic protein Von Willebrand factor plays a pivotal role in vascular health: quantitative or qualitative deficiencies of VWF can lead to bleeding, while elevated levels of VWF are associated with increased risk of thrombosis. Tight regulation of VWF secretion from WPBs is therefore essential to maintain vascular homeostasis. We used an unbiased proteomic screen to identify new components of the regulatory machinery that controls WPB exocytosis. Our data expand the endothelial SNARE protein network and provide a set of novel candidate WPB regulators that may contribute to regulation of VWF plasma levels and vascular health.
    Mesh-Begriff(e) Cells, Cultured ; Exocytosis/physiology ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Nerve Tissue Proteins/metabolism ; Protein Interaction Maps/physiology ; Proteomics ; Qa-SNARE Proteins/metabolism ; R-SNARE Proteins/metabolism ; Weibel-Palade Bodies/metabolism ; von Willebrand Factor/metabolism
    Chemische Substanzen Nerve Tissue Proteins ; Qa-SNARE Proteins ; R-SNARE Proteins ; STXBP5 protein, human ; von Willebrand Factor
    Sprache Englisch
    Erscheinungsdatum 2019-06-13
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2400835-7
    ISSN 1876-7737 ; 1874-3919
    ISSN (online) 1876-7737
    ISSN 1874-3919
    DOI 10.1016/j.jprot.2019.103417
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Weibel-Palade Body Localized Syntaxin-3 Modulates Von Willebrand Factor Secretion From Endothelial Cells.

    Schillemans, Maaike / Karampini, Ellie / van den Eshof, Bart L / Gangaev, Anastasia / Hofman, Menno / van Breevoort, Dorothee / Meems, Henriët / Janssen, Hans / Mulder, Aat A / Jost, Carolina R / Escher, Johanna C / Adam, Rüdiger / Carter, Tom / Koster, Abraham J / van den Biggelaar, Maartje / Voorberg, Jan / Bierings, Ruben

    Arteriosclerosis, thrombosis, and vascular biology

    2018  Band 38, Heft 7, Seite(n) 1549–1561

    Abstract: Objective: Endothelial cells store VWF (von Willebrand factor) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab effectors, and SNARE (soluble NSF attachment ... ...

    Abstract Objective: Endothelial cells store VWF (von Willebrand factor) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab effectors, and SNARE (soluble NSF attachment protein receptor) proteins. We have previously identified STXBP1 as the link between the Rab27A-Slp4-a complex on WPBs and the SNARE proteins syntaxin-2 and -3. In this study, we investigate the function of syntaxin-3 in VWF secretion.
    Approach and results: In human umbilical vein endothelial cells and in blood outgrowth endothelial cells (BOECs) from healthy controls, endogenous syntaxin-3 immunolocalized to WPBs. A detailed analysis of BOECs isolated from a patient with variant microvillus inclusion disease, carrying a homozygous mutation in
    Conclusions: Our data reveal syntaxin-3 as a novel WPB-associated SNARE protein that controls WPB exocytosis.
    Mesh-Begriff(e) Calcium/metabolism ; Cells, Cultured ; Cyclic AMP/metabolism ; Endothelial Cells/metabolism ; Endothelial Cells/ultrastructure ; Exocytosis ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Malabsorption Syndromes/diagnosis ; Malabsorption Syndromes/genetics ; Malabsorption Syndromes/metabolism ; Microvilli/genetics ; Microvilli/metabolism ; Microvilli/pathology ; Mucolipidoses/diagnosis ; Mucolipidoses/genetics ; Mucolipidoses/metabolism ; Mutation ; Qa-SNARE Proteins/genetics ; Qa-SNARE Proteins/metabolism ; R-SNARE Proteins/metabolism ; Secretory Pathway ; Signal Transduction ; Weibel-Palade Bodies/metabolism ; Weibel-Palade Bodies/ultrastructure ; von Willebrand Factor/metabolism
    Chemische Substanzen Qa-SNARE Proteins ; R-SNARE Proteins ; VAMP8 protein, human ; von Willebrand Factor ; Cyclic AMP (E0399OZS9N) ; Calcium (SY7Q814VUP)
    Sprache Englisch
    Erscheinungsdatum 2018-06-07
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1221433-4
    ISSN 1524-4636 ; 1079-5642
    ISSN (online) 1524-4636
    ISSN 1079-5642
    DOI 10.1161/ATVBAHA.117.310701
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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