Nuclear factor-κB (NF-κB) signaling participates in many biologic processes including immunity, inflammation, and cancer. Here we reported that tripartite motif-containing protein 56 (TRIM56), an E3 ligase enzyme, participated in TNFα-induced NF-κB signaling by interacting with TAK1. Overexpression of TRIM56 potentiated the activation of TNFα-induced NF-κB signaling, whereas knockdown of TRIM56 had an opposite effect. TRIM56 enhanced the ubiquitination of TAK1, specifically enhanced the M1-linked polyubiquitin chains to TAK1, leading to the tight interactions of the TAK1-IKKα complex. Consequently, the stimulation of TNFa and TRIM56 strengthened the interaction with TAK1. Furthermore, we found that the C terminal (CT) domain was the binding region of TRIM56, and the RING domain of TRIM56 was the E3 enzyme activity region which was important to the ubiquitination of TAK1. Together, these results reveal that TRIM56 positively regulates TNFα-induced NF-κB signaling by heightening the ubiquitination of TAK1 and provide new insight into the complicated mechanisms of the inflammatory and immune response.

核因子-κB (NF-κB) 信号传导参与许多生物过程，包括免疫、炎症和癌症。在这里，我们报道了包含三方基序的蛋白 56 (TRIM56)，一种 E3 连接酶，通过与 TAK1 相互作用参与 TNFα 诱导的 NF-κB 信号传导。TRIM56 的过表达增强了 TNFα 诱导的 NF-κB 信号传导的激活，而 TRIM56 的敲低具有相反的效果。TRIM56 增强了 TAK1 的泛素化，特别是增强了 M1 连接的多泛素链与 TAK1，导致 TAK1-IKKα 复合物的紧密相互作用。因此，TNFa 和 TRIM56 的刺激加强了与 TAK1 的相互作用。此外，我们发现C端（CT）域是TRIM56的结合区，TRIM56的RING结构域是对TAK1泛素化起重要作用的E3酶活性区。总之，这些结果表明，TRIM56 通过提高 TAK1 的泛素化正向调节 TNFα 诱导的 NF-κB 信号传导，并为炎症和免疫反应的复杂机制提供新的见解。