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Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury.
- Source :
-
Cell death discovery [Cell Death Discov] 2018 May 16; Vol. 4, pp. 60. Date of Electronic Publication: 2018 May 16 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- Vascular endothelial cadherin (VE-cad) expression at endothelial adherens junctions (AJs) regulates vascular homeostasis. Here we show that endothelial A20 is required for VE-cad expression at AJs to maintain and repair the injured endothelial barrier. In endothelial cell (EC)-restricted Tnfaip3 (A20) knockout ( A20 <superscript> ∆EC </superscript> ) mice, LPS challenge caused uncontrolled lung vascular leak and persistent sequestration of polymorphonuclear neutrophil (PMNs). Importantly, A20 <superscript> ∆EC </superscript> mice exhibited drastically reduced VE-cad expression in lungs compared with wild-type counterparts. Endothelial expression of wild-type A20 but not the deubiquitinase-inactive A20 mutant (A20 <superscript>C103A</superscript> ) prevented VE-cad ubiquitination, restored VE-cad expression, and suppressed lung vascular leak in A20 <superscript> ∆EC </superscript> mice. Interestingly, IRAK-M-mediated nuclear factor-κB (NF-κB) signaling downstream of TLR4 was required for A20 expression in ECs. interleukin-1 receptor-associated kinase M (IRAK-M) knockdown suppressed basal and LPS-induced A20 expression in ECs. Further, in vivo silencing of IRAK-M in mouse lung vascular ECs through the CRISPR-Cas9 system prevented expression of A20 and VE-cad while augmenting lung vascular leak. These results suggest that targeting of endothelial A20 is a potential therapeutic strategy to restore endothelial barrier integrity in the setting of acute lung injury.<br />Competing Interests: The authors declare that they have no conflict of interest.
Details
- Language :
- English
- ISSN :
- 2058-7716
- Volume :
- 4
- Database :
- MEDLINE
- Journal :
- Cell death discovery
- Publication Type :
- Academic Journal
- Accession number :
- 29796309
- Full Text :
- https://doi.org/10.1038/s41420-018-0056-3