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    Staphylococcus aureus-induced endothelial permeability and inflammation are mediated by microtubule destabilization

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    Author
    Karki, P.
    Ke, Y.
    Tian, Y.
    Date
    2019
    Journal
    The Journal of biological chemistry
    Publisher
    American Society for Biochemistry and Molecular Biology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1074/jbc.RA118.004030
    Abstract
    Staphylococcus aureus is a major etiological agent of sepsis and induces endothelial cell (EC) barrier dysfunction and inflammation, two major hallmarks of acute lung injury. However, the molecular mechanisms of bacterial pathogen-induced EC barrier disruption are incompletely understood. Here, we investigated the role of microtubules (MT) in the mechanisms of EC barrier compromise caused by heat-killed S. aureus (HKSA). Using a customized monolayer permeability assay in human pulmonary EC and MT fractionation, we observed that HKSA-induced barrier disruption is accompanied by MT destabilization and increased histone deacetylase-6 (HDAC6) activity resulting from elevated reactive oxygen species (ROS) production. Molecular or pharmacological HDAC6 inhibition rescued barrier function in HKSA-challenged vascular endothelium. The HKSA-induced EC permeability was associated with impaired MT-mediated delivery of cytoplasmic linker-associated protein 2 (CLASP2) to the cell periphery, limiting its interaction with adherens junction proteins. HKSA-induced EC barrier dysfunction was also associated with increased Rho GTPase activity via activation of MT-bound Rho-specific guanine nucleotide exchange factor-H1 (GEF-H1) and was abolished by HDAC6 down-regulation. HKSA activated the NF-κB proinflammatory pathway and increased the expression of intercellular and vascular cell adhesion molecules in EC, an effect that was also HDAC6-dependent and mediated, at least in part, by a GEF-H1/Rho-dependent mechanism. Of note, HDAC6 knockout mice or HDAC6 inhibitor-treated WT mice were partially protected from vascular leakage and inflammation caused by both HKSA or methicillin-resistant S. aureus (MRSA). Our results indicate that S. aureus-induced, ROS-dependent up-regulation of HDAC6 activity destabilizes MT and thereby activates the GEF-H1/Rho pathway, increasing both EC permeability and inflammation. © 2019 Karki et al.
    Keyword
    barrier disruption
    CLASP2
    GEF-H1
    Endothelium
    Histone Deacetylase 6
    Inflammation
    Lung Injury
    Microtubules
    Reactive Oxygen Species
    Staphylococcus aureus
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062593767&doi=10.1074%2fjbc.RA118.004030&partnerID=40&md5=0f619f35e6685a25f9f93c2ef3938d15; http://hdl.handle.net/10713/8628
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.RA118.004030
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