Show simple item record

dc.contributor.authorKarki, P.
dc.contributor.authorKe, Y.
dc.contributor.authorTian, Y.
dc.date.accessioned2019-03-29T14:47:32Z
dc.date.available2019-03-29T14:47:32Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85062593767&doi=10.1074%2fjbc.RA118.004030&partnerID=40&md5=0f619f35e6685a25f9f93c2ef3938d15
dc.identifier.urihttp://hdl.handle.net/10713/8628
dc.description.abstractStaphylococcus 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.en_US
dc.description.urihttps://dx.doi.org/10.1074/jbc.RA118.004030en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.relation.ispartofThe Journal of biological chemistry
dc.subjectbarrier disruptionen_US
dc.subjectCLASP2en_US
dc.subjectGEF-H1en_US
dc.subject.meshEndotheliumen_US
dc.subject.meshHistone Deacetylase 6en_US
dc.subject.meshInflammationen_US
dc.subject.meshLung Injuryen_US
dc.subject.meshMicrotubulesen_US
dc.subject.meshReactive Oxygen Speciesen_US
dc.subject.meshStaphylococcus aureusen_US
dc.titleStaphylococcus aureus-induced endothelial permeability and inflammation are mediated by microtubule destabilizationen_US
dc.typeArticleen_US
dc.identifier.doi10.1074/jbc.RA118.004030
dc.identifier.pmid30622143


This item appears in the following Collection(s)

Show simple item record