Linear ubiquitination improves NFAT1 protein stability and facilitates NFAT1 signalling in Kawasaki disease
Linear ubiquitination improves NFAT1 protein stability and facilitates NFAT1 signalling in Kawasaki disease
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DOI：
10.1111/febs.16749
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发表时间：
2023-02
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影响因子：
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通讯作者：
Ying Miao;Guang-Hui Qian;Renxia Zhang;Yukang Yuan;Yibo Zuo;Yue-yue Ding;Xuan Li;Yunjia Tang;Huizhen Zheng;H. Lv
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作者：
Ying Miao;Guang-Hui Qian;Renxia Zhang;Yukang Yuan;Yibo Zuo;Yue-yue Ding;Xuan Li;Yunjia Tang;Huizhen Zheng;H. Lv
NFAT 1在T细胞发育和活化中的作用是众所周知的。到目前为止，NFAT 1的磷酸化已被广泛研究，但NFAT 1的其他翻译后修饰仍在很大程度上未知。在本研究中，我们报道了NFAT 1是线性泛素链组装复合物（LUBAC）的线性泛素化底物。LUBAC促进NFAT 1线性泛素化，这反过来又抑制NFAT 1的K48连接的多聚泛素化，从而增加NFAT 1蛋白的稳定性。有趣的是，川崎患者的NFAT 1线性泛素化水平上调。进一步研究表明，川崎患者HOIL-1 L的mRNA水平升高。这些发现揭示了LUBAC的线性泛素化底物和NFAT 1的线性泛素化在川崎病中的重要生物学功能，因此可能为川崎病的治疗提供新的策略。
NFAT1 is known for its roles in T cell development and activation. So far, the phosphorylation of NFAT1 has been extensively studied, but the other post‐translational modifications of NFAT1 remain largely unknown. In this study, we reported that NFAT1 is a linearly ubiquitinated substrate of linear ubiquitin chain assembly complex (LUBAC). LUBAC promoted NFAT1 linear ubiquitination, which in turn inhibited K48‐linked polyubiquitination of NFAT1 and therefore increased NFAT1 protein stability. Interestingly, the linear ubiquitination levels of NFAT1 in patients with the Kawasaki disease were upregulated. Further studies demonstrated that the patients with the Kawasaki disease had increased mRNA levels of HOIL‐1L. These findings revealed a linearly ubiquitinated substrate of LUBAC and an important biological function of NFAT1 linear ubiquitination in the Kawasaki disease and therefore may provide a novel strategy for the treatment of the Kawasaki disease.