期刊
FASEB JOURNAL
卷 29, 期 5, 页码 1869-1878出版社
WILEY
DOI: 10.1096/fj.14-258533
关键词
NF-kappa B; molecular mechanism; receptor interacting protein
资金
- British Heart Foundation
- National Heart and Lung Institute, Imperial College London, United Kingdom
- U.S. National Institutes of Health R01 Grant [HL080130, DK063275]
- Austrian Science Fund Grant [J3398-BW23]
A20 protects against pathologic vascular remodeling by inhibiting the inflammatory transcription factor NF-kappa B. A20's function has been attributed to ubiquitin editing of receptor-interacting protein 1 (RIP1) to influence activity/stability. The validity of this mechanism was tested using a murine model of transplant vasculopathy and human cells. Mouse C57BL/6 aortae transduced with adenoviruses containing A20 (or beta-galactosidase as a control) were allografted into major histocompatibility complex-mismatched BALB/c mice. Primary endothelial cells, smooth muscle cells, or transformed epithelial cells (all human) were transfected with wild-type A20 or with catalytically inactive mutants as a control. NF-kappa B activity and intracellular localization of RIP1 was monitored by reporter gene assay, immunofluorescent staining, and Western blotting. Native and catalytically inactive versions of A20 had similar inhibitory effects on NF-kappa B activity (-70% vs. -76%; P > 0.05). A20 promoted localization of RIP1 to insoluble aggresomes in murine vascular allografts and in human cells (53% vs. 0%) without altering RIP1 expression, and this process was increased by the assembly of polyubiquitin chains (87% vs. 28%; P < 0.05). A20 captures polyubiquitinated signaling intermediaries in insoluble aggresomes, thus reducing their bioavailability for downstream NF-kappa B signaling. This novel mechanism contributes to protection from vasculopathy in transplanted organs treated with exogenous A20.
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