The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapter NEMO, AZI2 is recruited later via deubiquitinase A20. In summary, our data show that TANK and AZI2 cooperatively sustain TBK1 activity during different stages of TNF receptor assembly to protect against autoinflammation.

细胞因子 TNF 可触发高度促炎性 RIPK1 依赖性细胞死亡。在这里，我们表明两种衔接蛋白 TANK 和 AZI2 通过调节 TBK1 激酶的激活来抑制 TNF 诱导的细胞死亡。缺乏 TANK 或 AZI2 的小鼠没有表现出明显的表型。相反，缺乏两种接头的动物出生时呈亚孟德尔比率，并患有严重的多器官炎症、抗体产生过多、雄性不育和早期死亡，这可以通过 TNFR1 缺陷来挽救，并通过表达激酶死亡形式的 RIPK1 得到显着改善。从机制上讲，TANK 和 AZI2 都将 TBK1 募集到 TNF 受体信号转导复合物中，但由于与不同的复合物组分相互作用，因此具有不同的动力学。虽然 TANK 直接与接头 NEMO 结合，但 AZI2 稍后通过去泛素酶 A20 募集。总之，我们的数据表明，TANK 和 AZI2 在 TNF 受体组装的不同阶段协同维持 TBK1 活性，以防止自身炎症。