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
Institute of Biochemical Sciences, National Taiwan University, Taipei 115, Taiwan.
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):15078-15083. doi: 10.1073/pnas.1618773114. Epub 2016 Dec 13.
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.
Toll样受体介导的NF-κB激活是血管内皮细胞（ECs）对促氧化和促炎刺激的主要固有免疫反应。我们发现，具有叉头相关结构域的肿瘤坏死因子-α受体相关因子相互作用蛋白（TIFA）是ECs中核苷酸寡聚化结构域样受体家族含pyrin结构域蛋白3（NLRP3）炎性小体起始（信号1）和激活（信号2）信号的调节因子。氧化应激和炎症应激，如易致动脉粥样硬化的血流和高脂血症，在体外和体内均可诱导并激活TIFA。对于信号1的起始，固醇调节元件结合蛋白2反式激活TIFA，进而诱导NF-κB激活并增强NLRP3炎性小体成分的转录。对于信号2的激活，Akt参与TIFA第9位苏氨酸的磷酸化，这对于TIFA-TIFA同源寡聚化至关重要。如激活的ECs中TIFA与半胱天冬酶-1之间的相互作用所示，第9位苏氨酸磷酸化依赖性TIFA寡聚化促进了NLRP3炎性小体的高阶组装。我们的结果表明，TIFA通过增强信号1和信号2来增强和放大NLRP3炎性小体，是内皮固有免疫反应中的关键介质。
