TRAF6 通过稳定 STAT6 促进 IL-4 诱导的 M2 巨噬细胞活化。
TRAF6 promotes IL-4-induced M2 macrophage activation by stabilizing STAT6.
机构信息
Department of Biomedical Engineering, The Fifth Medical Center of PLA General Hospital, Beijing 100071, China.
Department of Biomedical Engineering, The Fifth Medical Center of PLA General Hospital, Beijing 100071, China.
出版信息
Mol Immunol. 2020 Nov;127:223-229. doi: 10.1016/j.molimm.2020.09.001. Epub 2020 Oct 2.
E3 ligase TRAF6 plays a critical role in TLRs trigged M1 macrophage activation. However, the function of TRAF6 in IL-4-induced M2 macrophage activation has not been illuminated. We report here that deficiency of TRAF6 significantly impaired IL-4-induced genes expression in macrophage. Mechanistically, TRAF6 mediated the protein stability of STAT6, a key factor in IL-4 signaling. Overexpression of TRAF6 increased STAT6 protein level, conversely, knockdown or knockout of endogenous TRAF6 decreased it. Further study showed that TRAF6 bound STAT6 by TRAF6 C domain and reduced K48-ubiquitination of STAT6 which could induce degradation of STAT6, explaining why TRAF6 could conduct STAT6 stability. Intriguingly, the E3 ligase activity of TRAF6 was dispensable for stabilizing STAT6, despite TRAF6 promoted its K63 ubiquitination. These results indicate that TRAF6 is essential for STAT6 stability in IL-4 signaling and may act as a positive regulator in both M1 and M2 polarization.
E3 连接酶 TRAF6 在 TLRs 触发的 M1 巨噬细胞活化中起着关键作用。然而，TRAF6 在 IL-4 诱导的 M2 巨噬细胞活化中的功能尚未阐明。我们在这里报告，TRAF6 的缺失显著损害了巨噬细胞中 IL-4 诱导的基因表达。在机制上，TRAF6 介导了 STAT6 的蛋白稳定性，STAT6 是 IL-4 信号通路中的关键因子。TRAF6 的过表达增加了 STAT6 蛋白水平，相反，内源性 TRAF6 的敲低或敲除降低了它。进一步的研究表明，TRAF6 通过 TRAF6 C 结构域与 STAT6 结合，并减少 STAT6 的 K48 泛素化，从而诱导 STAT6 的降解，这解释了为什么 TRAF6 可以稳定 STAT6。有趣的是，TRAF6 的 E3 连接酶活性对于稳定 STAT6 是可有可无的，尽管 TRAF6 促进了其 K63 泛素化。这些结果表明，TRAF6 是 IL-4 信号中 STAT6 稳定性所必需的，并且可能在 M1 和 M2 极化中都作为一个正调节剂发挥作用。
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