The TNFα-induced NF-κB signaling pathway plays critical roles in multiple biological processes. Extensive studies have explored the mechanisms regulating this signaling cascade, and identified an E2 complex, Uev1A-Ubc13, that mediates K63-linked poly-Ub chain formation and thus recruits NEMO to activate the signaling transduction. In this study, we demonstrate that the Uev1A-Ubc13 complex simultaneously serves as a repressor of the NF-κB pathway. It was found that cells overexpressing UEV1A silence the signal cascade earlier than control cells. Importantly, UEV1A overexpression enhances TACE maturation to shed the TNFα receptor. The Uev1A-Ubc13 complex interacts with RHBDF2, a key factor promoting TACE maturation, and inhibition of the Uev1A-Ubc13 activity interferes with RHBDF2-promoted TACE maturation. Furthermore, upon TNFα stimulation, the Uev1A-Ubc13 complex cooperates with CHIP to promote K63-linked ubiquitination of RHBDF2, enhancing its activity toward TACE maturation and subsequently blocking TNFα-induced NF-κB signaling.

TNFα诱导的NF-κB信号通路在多种生物学过程中起着至关重要的作用。广泛的研究探索了调节该信号级联反应的机制，并鉴定了介导K63连接的多Ub链形成并因此募集NEMO来激活信号转导的E2复合物Uev1A-Ubc13。在这项研究中，我们证明了Uev1A-Ubc13复合体同时充当NF-κB通路的阻遏物。发现过表达UEV1A的细胞比控制细胞更早地使信号级联沉默。重要的是，UEV1A过表达会增强TACE的成熟，从而使TNFα受体脱落。Uev1A-Ubc13复合物与RHBDF2相互作用，这是促进TACE成熟的关键因素，而对Uev1A-Ubc13活性的抑制会干扰RHBDF2促进的TACE成熟。此外，在TNFα刺激下，Uev1A-Ubc13复合物与CHIP协同作用，促进RHBDF2的K63连接泛素化，增强其对TACE成熟的活性，并随后阻断TNFα诱导的NF-κB信号传导。