Henan International Joint Laboratory of Children's Infectious Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, Zhengzhou, 450000, China.
School of Life Sciences, Henan University, Kaifeng 475000, China.
Int J Biol Macromol. 2022 Oct 31;219:571-578. doi: 10.1016/j.ijbiomac.2022.08.019. Epub 2022 Aug 8.
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）信号参与许多生物学过程，包括免疫、炎症和癌症。在这里，我们报告三结构域蛋白 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。TRIM56 的过表达增强了 TNFα 诱导的 NF-κB 信号的激活，而 TRIM56 的敲低则产生相反的效果。TRIM56 增强了 TAK1 的泛素化，特别是增强了 M1 连接的多聚泛素链到 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）结构域是 TRIM56 的结合区域，而 TRIM56 的 RING 结构域是 E3 酶活性区域，对 TAK1 的泛素化很重要。总之，这些结果表明 TRIM56 通过增强 TAK1 的泛素化来正向调节 TNFα 诱导的 NF-κB 信号，并为炎症和免疫反应的复杂机制提供了新的见解。
