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TIFA has dual functions in Helicobacter pylori-induced classical and alternative NF-κB pathways
EMBO Reports ( IF 6.5 ) Pub Date : 2021-07-30 , DOI: 10.15252/embr.202152878
Gunter Maubach 1 , Michelle C C Lim 1 , Olga Sokolova 1 , Steffen Backert 2 , Thomas F Meyer 3, 4 , Michael Naumann 1
Affiliation  

Helicobacter pylori infection constitutes one of the major risk factors for the development of gastric diseases including gastric cancer. The activation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) via classical and alternative pathways is a hallmark of H. pylori infection leading to inflammation in gastric epithelial cells. Tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA) was previously suggested to trigger classical NF-κB activation, but its role in alternative NF-κB activation remains unexplored. Here, we identify TRAF6 and TRAF2 as binding partners of TIFA, contributing to the formation of TIFAsomes upon H. pylori infection. Importantly, the TIFA/TRAF6 interaction enables binding of TGFβ-activated kinase 1 (TAK1), leading to the activation of classical NF-κB signaling, while the TIFA/TRAF2 interaction causes the transient displacement of cellular inhibitor of apoptosis 1 (cIAP1) from TRAF2, and proteasomal degradation of cIAP1, to facilitate the activation of the alternative NF-κB pathway. Our findings therefore establish a dual function of TIFA in the activation of classical and alternative NF-κB signaling in H. pylori-infected gastric epithelial cells.

中文翻译:

TIFA 在幽门螺杆菌诱导的经典和替代 NF-κB 通路中具有双重功能

幽门螺杆菌感染是包括胃癌在内的胃病发展的主要危险因素之一。通过经典和替代途径激活活化 B 细胞 (NF-κB) 的核因子-kappa-轻链增强子是幽门螺杆菌感染导致胃上皮细胞炎症的标志。肿瘤坏死因子受体相关因子 (TRAF) 与叉头相关结构域 (TIFA) 的相互作用蛋白先前被认为可触发经典的 NF-κB 激活,但其在替代 NF-κB 激活中的作用仍未探索。在这里,我们将 TRAF6 和 TRAF2 确定为 TIFA 的结合伙伴,有助于在幽门螺杆菌上形成 TIFAsomes感染。重要的是,TIFA/TRAF6 相互作用能够结合 TGFβ 活化激酶 1 (TAK1),从而激活经典的 NF-κB 信号,而 TIFA/TRAF2 相互作用导致细胞凋亡抑制剂 1 (cIAP1) 从TRAF2 和 cIAP1 的蛋白酶体降解,以促进替代 NF-κB 途径的激活。因此,我们的研究结果确立了 TIFA 在激活幽门螺杆菌感染的胃上皮细胞中经典和替代 NF-κB 信号传导方面的双重功能。
更新日期:2021-09-06
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