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A20 suppresses vascular inflammation by recruiting proinflammatory signaling
molecules to intracellular aggresomes
#MMPMID25667218
Enesa K
; Moll HP
; Luong L
; Ferran C
; Evans PC
FASEB J
2015[May]; 29
(5
): 1869-78
PMID25667218
show ga
A20 protects against pathologic vascular remodeling by inhibiting the
inflammatory transcription factor NF-?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 ?-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-?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-?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-?B signaling. This novel mechanism
contributes to protection from vasculopathy in transplanted organs treated with
exogenous A20.
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