CSN5 inhibition triggers inflammatory signaling and Rho/ROCK-dependent loss of endothelial integrity
| Autor: | Manon C. A. Pronk, Astrid M. van der Sar, Jan van Bezu, Igor Kovačević, Kin K. Jim, Peter L. Hordijk, Jisca Majolée |
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| Přispěvatelé: | Physiology, ACS - Atherosclerosis & ischemic syndromes, Medical Microbiology and Infection Prevention, AII - Inflammatory diseases, ACS - Microcirculation |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
RHOA Neutrophils RHOB lcsh:Medicine RHO signalling 0302 clinical medicine NF-KappaB Inhibitor alpha Ubiquitin lcsh:Science rhoB GTP-Binding Protein Vascular diseases Zebrafish rho-Associated Kinases Multidisciplinary biology Chemistry Intracellular Signaling Peptides and Proteins Intercellular Adhesion Molecule-1 Up-Regulation Cell biology medicine.anatomical_structure Cullin Endothelium Green Fluorescent Proteins Cyclopentanes Article 03 medical and health sciences Human Umbilical Vein Endothelial Cells medicine Animals Humans Inflammation COP9 Signalosome Complex lcsh:R HEK 293 cells NF-kappa B p50 Subunit IκBα HEK293 Cells Pyrimidines 030104 developmental biology Gene Expression Regulation biology.protein lcsh:Q Endothelium Vascular Neddylation rhoA GTP-Binding Protein 030217 neurology & neurosurgery Peptide Hydrolases |
| Zdroj: | Majolée, J, Pronk, M C A, Jim, K K, van Bezu, J S M, van der Sar, A M, Hordijk, P L & Kovačević, I 2019, ' CSN5 inhibition triggers inflammatory signaling and Rho/ROCK-dependent loss of endothelial integrity ', Scientific Reports, vol. 9, no. 1, 8131 . https://doi.org/10.1038/s41598-019-44595-4 Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) Scientific Reports, 9(1):8131. Nature Publishing Group |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-44595-4 |
| Popis: | RhoGTPases regulate cytoskeletal dynamics, migration and cell-cell adhesion in endothelial cells. Besides regulation at the level of guanine nucleotide binding, they also undergo post-translational modifications, for example ubiquitination. RhoGTPases are ubiquitinated by Cullin RING ligases which are in turn regulated by neddylation. Previously we showed that inhibition of Cullin RING ligase activity by the neddylation inhibitor MLN4924 is detrimental for endothelial barrier function, due to accumulation of RhoB and the consequent induction of contractility. Here we analyzed the effect of pharmacological activation of Cullin RING ligases on endothelial barrier integrity in vitro and in vivo. CSN5i-3 induced endothelial barrier disruption and increased macromolecule leakage in vitro and in vivo. Mechanistically, CSN5i-3 strongly induced the expression and activation of RhoB and to lesser extent of RhoA in endothelial cells, which enhanced cell contraction. Elevated expression of RhoGTPases was a consequence of activation of the NF-κB pathway. In line with this notion, CSN5i-3 treatment decreased IκBα expression and increased NF-κB-mediated ICAM-1 expression and consequent adhesion of neutrophils to endothelial cells. This study shows that sustained neddylation of Cullin RING-ligases leads to activation the NF-κB pathway in endothelial cells, elevated expression of RhoGTPases, Rho/ROCK-dependent activation of MLC and disruption of the endothelial barrier. |
| Databáze: | OpenAIRE |
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