Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, PR China.
Department of Pharmacology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, PR China.
Cell Death Differ. 2021 Nov;28(11):3077-3091. doi: 10.1038/s41418-021-00803-1. Epub 2021 May 20.
Protein ubiquitination plays an important role in the regulation of TGF-β-activated kinase 1 (TAK1)-mediated NF-κB activation. It is well established that TAK1 activation is tightly regulated with its binding partners, TAK1-binding proteins (TAB1-3). However, the tight regulation of TAK1 activation remains elusive. Here, using Trim26-knockout mice and Trim26-transgenic mice, we found that TRIM26 acts as a positive regulator of TAK1 activation by ubiquitinating its binding partner TAB1. Knockout of Trim26 inhibited TAK1 activation and downstream kinases activation, thus decreasing the induction of proinflammatory cytokines following LPS, TNF-α, and IL-1β stimulation. Mechanistically, TRIM26 catalyzes the K11-linked polyubiquitination of TAB1 at Lys294, Lys319, and Lys335 to enhance the activation of TAK1 and subsequent NF-κB and MAPK signaling. Consequently, Trim26 deficiency protects mice from LPS-induced septic shock in vivo. Moreover, Trim26 deficiency attenuates the severity of dextran sodium sulfate (DSS)-induced colitis. Thus, these finding provides a novel insight into how TAK1 activation is regulated through TRIM26-mediated ubiquitination of TAB1 and reveals the new function of TRIM26 in the regulation of the inflammatory innate immune response.
蛋白质泛素化在调节 TGF-β激活激酶 1（TAK1）介导的 NF-κB 激活中起着重要作用。众所周知，TAK1 的激活受到其结合伙伴 TAK1 结合蛋白（TAB1-3）的严格调控。然而，TAK1 激活的严格调控仍然难以捉摸。在这里，我们使用 Trim26 敲除小鼠和 Trim26 转基因小鼠发现，TRIM26 通过泛素化其结合伙伴 TAB1 作为 TAK1 激活的正调节剂。Trim26 的敲除抑制了 TAK1 的激活和下游激酶的激活，从而减少了 LPS、TNF-α 和 IL-1β刺激后促炎细胞因子的诱导。在机制上，TRIM26 催化 TAB1 在 Lys294、Lys319 和 Lys335 上的 K11 连接多泛素化，以增强 TAK1 的激活以及随后的 NF-κB 和 MAPK 信号转导。因此，Trim26 缺陷保护小鼠免受 LPS 诱导的败血症休克。此外，Trim26 缺陷减轻了葡聚糖硫酸钠（DSS）诱导的结肠炎的严重程度。因此，这些发现为 TAK1 激活如何通过 TRIM26 介导的 TAB1 泛素化调节提供了新的见解，并揭示了 TRIM26 在调节炎症先天免疫反应中的新功能。
