Transcriptional factor nuclear factor κB (NF-κB) can be activated by various intracellular or extracellular stimuli and its dysregulation leads to pathological conditions, such as neurodegenerative disorders, infection, and cancer. The carboxyl terminus of HSC70-interacting protein (CHIP), a pathogenic gene of spinocerebellar autosomal recessive 16 (SCAR16), plays an important roles in protein degradation, trafficking, and multiple signaling transductions. It has been reported that CHIP participates in the regulation of NF-κB signaling, and the mutant of CHIP (p.T246M) leads to the occurrence of SCAR16. However, the detailed mechanism of CHIP and CHIP (p.T246M) in the regulation of NF-κB signaling in neurological disorders remains unclear. Here, we found that CHIP promoted the activation of NF-κB signaling, while the knockdown had the opposite effect. Furthermore, CHIP interacted with TAK1 and targeted it for K63-linked ubiquitination. Finally, CHIP enhanced the interaction between TAK1 and NEMO. However, CHIP (p.T246M) couldn’t upregulate NF-κB signaling, potentiate the ubiquitination of TAK1, and enhance the interactions. Taken together, our study demonstrated for the first time that CHIP positively regulates NF-κB signaling by targeting TAK1 and enhancing its K63-linked ubiquitination.

转录因子核因子κB（NF-κB）可以被各种细胞内或细胞外刺激激活，其失调会导致病理状况，如神经退行性疾病、感染和癌症。HSC70 相互作用蛋白 (CHIP) 的羧基末端是脊髓小脑常染色体隐性遗传 16 (SCAR16) 的致病基因，在蛋白质降解、运输和多重信号转导中起着重要作用。已有报道CHIP参与NF-κB信号的调控，CHIP突变体（p.T246M）导致SCAR16的发生。然而，CHIP 和 CHIP (p.T246M) 在神经系统疾病中调节 NF-κB 信号传导的详细机制仍不清楚。在这里，我们发现 CHIP 促进了 NF-κB 信号的激活，而击倒产生了相反的效果。此外，CHIP 与 TAK1 相互作用并将其靶向 K63 相关泛素化。最后，CHIP 增强了 TAK1 和 NEMO 之间的相互作用。然而，CHIP (p.T246M) 不能上调 NF-κB 信号，增强 TAK1 的泛素化，并增强相互作用。总之，我们的研究首次证明 CHIP 通过靶向 TAK1 并增强其 K63 相关泛素化来正向调节 NF-κB 信号传导。