Author:
Lin Ting-Yang,Wei Tong-You Wade,Li Shuai,Wang Shen-Chih,He Ming,Martin Marcy,Zhang Jiao,Shentu Tzu-Pin,Xiao Han,Kang Jian,Wang Kuei-Chun,Chen Zhen,Chien Shu,Tsai Ming-Daw,Shyy John Y.-J.
Abstract
Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to prooxidative and proinflammatory stimuli. We identified that TNF-α 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-κB 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.
Funder
HHS | National Institutes of Health
Taiwan National Health Research Institute
Ministry of Science and Technology, Taiwan
Publisher
Proceedings of the National Academy of Sciences
Cited by
41 articles.
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