ArticleScientific reports2019
CSN5 inhibition triggers inflammatory signaling and Rho/ROCK-dependent loss of endothelial integrity.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 22 citations in OpenAlex.
- COP9 signalosome deneddylation activity is required for proliferation but not dedifferentiation of vascular smooth muscle cells in neointimal hyperplasia.American journal of physiology. Heart and circulatory physiology · 2026Article
- [Differential expression of NEDD8 in different pathological types of chronic rhinosinusitis with nasal polyps].Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery · 2023Article
- The C-terminal tail of CSNAP attenuates the CSN complex.Life science alliance · 2023Article
- The COP9 signalosome reduces neuroinflammation and attenuates ischemic neuronal stress in organotypic brain slice culture model.Cellular and molecular life sciences : CMLS · 2023Article
- Regulatory mechanisms and therapeutic potential of JAB1 in neurological development and disorders.Molecular medicine (Cambridge, Mass.) · 2023Review
- Role of HDAC6 inhibition in sepsis-induced acute respiratory distress syndrome (Review).Experimental and therapeutic medicine · 2021Review
- Inhibition of HDAC6 Activity Protects Against Endothelial Dysfunction and AtherogenesisFrontiers in physiology · 2021Article
- Regulation of Rho GTPases in the Vasculature by Cullin3-Based E3 Ligase Complexes.Frontiers in cell and developmental biology · 2021Review
- The pivotal roles of neddylation pathway in immunoregulation.Immunity, inflammation and disease · 2020Review
- COP9 signalosome is an essential and druggable parasite target that regulates protein degradation.PLoS pathogens · 2020Article
- Rho-Kinase 1/2 Inhibition Prevents Transforming Growth Factor-β-Induced Effects on Pulmonary Remodeling and Repair.Frontiers in pharmacology · 2020Article
- Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases.Biomolecules · 2019Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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