A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes. Issue 5 (9th February 2015)

• Record Type: Journal Article
• Authors: Enesa, Karine; Moll, Herwig P.; Luong, Le; Ferran, Christiane; Evans, Paul C.
• Is Part Of: FASEB journal. Volume 29:Issue 5(2015)
• Page Start: 1869
• Page End: 1878
• Publication Date: 2015-02-09
• Subjects: NF‐κB -- molecular mechanism -- receptor interacting protein; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.14-258533
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: A20 protects against pathologic vascular remodeling by inhibiting the inflammatory transcription factor NF‐κB. 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 β‐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‐κB 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‐κB 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‐κB signaling. This novel mechanism contributes to protection from vasculopathy in transplanted organs treated with exogenous A20.—Enesa, K., Moll, H. P., Luong, L., Ferran, C., Evans, P. C. A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes. FASEB J. 29, 1869‐1878 (2015). www.fasebj.org