Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China; and.
Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China; and
J Immunol. 2018 Jun 15;200(12):4117-4124. doi: 10.4049/jimmunol.1800172. Epub 2018 May 4.
Linear ubiquitin chain assembly complex plays an important role in regulating TNF-α signaling activation by modifying target proteins with linear (M1-linked) ubiquitin chains. In this study, we report that the epidermis-specific knockout (KO) of RNF31, the catalytic subunit of linear ubiquitin chain assembly complex, results in an early postnatal lethality in mice due to severe skin inflammation. The inflammation was mainly triggered by TNF-α-induced apoptosis in RNF31 KO keratinocytes. Mechanistically, the deficiency of RNF31 not only impaired TNF-α-induced NF-κB activation, but also significantly increased apoptosis. Consistently, deleting TNF receptor 1 could rescue the lethality of RNF31 epidermis-specific KO mice and also the skin inflammation. Collectively, our study provides an in vivo insight that linear ubiquitination is critical for maintaining the homeostasis of keratinocytes, which will shed light on designing therapeutic compounds to treat skin inflammation.
线性泛素链组装复合物在通过用线性（M1 连接）泛素链修饰靶蛋白来调节 TNF-α 信号激活方面起着重要作用。在这项研究中，我们报告说，线性泛素链组装复合物的催化亚基 RNF31 的表皮特异性敲除（KO）导致小鼠在出生后因严重的皮肤炎症而早期死亡。炎症主要是由 RNF31 KO 角质细胞中 TNF-α 诱导的细胞凋亡引发的。从机制上讲，RNF31 的缺乏不仅损害了 TNF-α诱导的 NF-κB 激活，而且还显著增加了细胞凋亡。一致地，删除 TNF 受体 1 可以挽救 RNF31 表皮特异性 KO 小鼠的致死性和皮肤炎症。总之，我们的研究提供了一种体内见解，即线性泛素化对于维持角质细胞的动态平衡至关重要，这将为设计治疗皮肤炎症的治疗化合物提供启示。
