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2016 ; 113
(52
): 15078-15083
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TIFA as a crucial mediator for NLRP3 inflammasome
#MMPMID27965388
Lin TY
; Wei TW
; Li S
; Wang SC
; He M
; Martin M
; Zhang J
; Shentu TP
; Xiao H
; Kang J
; Wang KC
; Chen Z
; Chien S
; Tsai MD
; Shyy JY
Proc Natl Acad Sci U S A
2016[Dec]; 113
(52
): 15078-15083
PMID27965388
show ga
Toll-like receptor-mediated NF-?B activation is a major innate immune reaction of
vascular endothelial cells (ECs) in response to prooxidative and proinflammatory
stimuli. We identified that TNF-? receptor-associated factor-interacting protein
with a forkhead-associated domain (TIFA) is a regulator of priming (signal 1) and
activating (signal 2) signals of nucleotide oligomerization domain-like receptor
family pyrin domain-containing protein 3 (NLRP3) inflammasome in ECs. Oxidative
and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and
activate TIFA in vitro and in vivo. For the priming of signal 1, sterol
regulatory element-binding protein 2 transactivates TIFA, which in turn induces
NF-?B activation and augments the transcription of NLRP3 inflammasome components.
For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation,
which is essential for TIFA-TIFA homophilic oligomerization. Thr9
phosphorylation-dependent TIFA oligomerization facilitates the higher-order
assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and
caspase-1 in the activated ECs. Our results suggest that TIFA is a crucial
mediator in the endothelial innate immune response by potentiating and amplifying
NLRP3 inflammasome via augmenting signals 1 and 2.
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