Ubiquitin-based modifications in endothelial cell–cell contact and inflammation

Abstract

Endothelial cell-cell contacts are essential for vascular integrity and physiology, protecting tissues and organs from edema and uncontrolled invasion of inflammatory cells. The vascular endothelial barrier is dynamic, but its integrity is preserved through a tight control at different levels. Inflammatory cytokines and G-protein-coupled receptor agonists, such as histamine, reduce endothelial integrity and increase vascular leakage. This is due to elevated myosin-based contractility, in conjunction with phosphorylation of proteins at cell-cell contacts. Conversely, reducing contractility stabilizes or even increases endothelial junctional integrity. Rho GTPases are key regulators of such cytoskeletal dynamics and endothelial cell-cell contacts. In addition to signaling-induced regulation, the expression of junctional proteins, such as occludin, claudins and vascular endothelial cadherin, also controls endothelial barrier function. There is increasing evidence that, in addition to protein phosphorylation, ubiquitylation (also known as ubiquitination) is an important and dynamic post-translational modification that regulates Rho GTPases, junctional proteins and, consequently, endothelial barrier function. In this Review, we discuss the emerging role of ubiquitylation and deubiquitylation events in endothelial integrity and inflammation. The picture that emerges is one of increasing complexity, which is both fascinating and promising given the clinical relevance of vascular integrity in the control of inflammation, and of tissue and organ damage.

Peer Review #3 of "A 22-amino-acid peptide regulates tight junctions through occludin and cell apoptosis (v0.1)"

“…Wong et al found that the 44-amino-acid peptide in the second extracellular loop of occludin had no effect on the expression level of ZO-1, ZO-2, or cingulin in the Xenopus kidney epithelial cell line A6 [21]. Therefore, in the present study, only the dynamic expression of occludin was quantitatively analyzed when investigating the mechanism underlying the destruction and recovery of TJ Manuscript to be reviewed protein degradation [32]. Occludin phosphorylation and ubiquitination regulate TJ [33].…”

Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

“…Suggesting defective junctional protein degradation and turnover in autophagy impaired ECs, these findings are in agreement with the targeting of junctional components by autophagy mechanisms reported in other cell types ( Bejarano et al., 2012 ; Nighot et al., 2015 ; Wang et al., 2014 ). Regulated by a plethora of post-translational modifications, including phosphorylation and ubiquitination, vesicular trafficking of EC junctional components dictates their cellular localization and functional properties ( Majolée et al., 2019 ; Wessel et al., 2014 ). Notably, both phosphorylation and ubiquitination act as molecular signals that can target specific pools of proteins to autophagic compartments ( Bejarano et al., 2012 ; Levine and Kroemer, 2019 ).…”

A 22-amino-acid peptide regulates tight junctions through occludin and cell apoptosis

“…There are three possible reasons for the decrease in protein expression. The first reason is protein degradation (Majolee, Kovacevic & Hordijk, 2019). Occludin phosphorylation and ubiquitination regulate TJ (Murakami, Felinski & Antonetti, 2009).…”