Staphylococcus aureus-induced endothelial permeability and inflammation are mediated by microtubule destabilization
JournalThe Journal of biological chemistry
PublisherAmerican Society for Biochemistry and Molecular Biology
MetadataShow full item record
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.
Histone Deacetylase 6
Reactive Oxygen Species
Identifier to cite or link to this itemhttps://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
- Microtubule destabilization caused by particulate matter contributes to lung endothelial barrier dysfunction and inflammation.
- Authors: Karki P, Meliton A, Sitikov A, Tian Y, Ohmura T, Birukova AA
- Issue date: 2019 Jan
- SOCS3-microtubule interaction via CLIP-170 and CLASP2 is critical for modulation of endothelial inflammation and lung injury.
- Authors: Karki P, Ke Y, Zhang CO, Li Y, Tian Y, Son S, Yoshimura A, Kaibuchi K, Birukov KG, Birukova AA
- Issue date: 2021 Jan-Jun
- Oxidative stress contributes to lung injury and barrier dysfunction via microtubule destabilization.
- Authors: Kratzer E, Tian Y, Sarich N, Wu T, Meliton A, Leff A, Birukova AA
- Issue date: 2012 Nov
- Control of vascular permeability by atrial natriuretic peptide via a GEF-H1-dependent mechanism.
- Authors: Tian X, Tian Y, Gawlak G, Sarich N, Wu T, Birukova AA
- Issue date: 2014 Feb 21
- GEF-H1 is involved in agonist-induced human pulmonary endothelial barrier dysfunction.
- Authors: Birukova AA, Adyshev D, Gorshkov B, Bokoch GM, Birukov KG, Verin AD
- Issue date: 2006 Mar