Lys29-linkage of ASK1 by Skp1-Cullin 1-Fbxo21 ubiquitin ligase complex is required for antiviral innate response
Lys29-linkage of ASK1 by Skp1-Cullin 1-Fbxo21 ubiquitin ligase complex is required for antiviral innate response
复制标题
Skp1-Cullin 1-Fbxo21 泛素连接酶复合物对 ASK1 的 Lys29 连接是抗病毒先天反应所必需的
DOI：
10.7554/elife.14087
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发表时间：
2016-04-11
期刊：
影响因子：
7.7
通讯作者：
Wang, Jianli
中科院分区：
文献类型：
--
作者：
Yu, Zhou;Chen, Taoyong;Wang, Jianli
泛素连接酶调控的蛋白质泛素化在先天免疫中起着重要作用。然而，先天反应中泛素化的关键调节因子以及新型泛素化(除Lys48和Lys63连锁外)在控制先天信号中的作用尚不清楚。在这里，我们报道了F-box Only蛋白Fbxo21，SCF(Skp1 cull F-box Protein)复合体的一个功能未知的成分，促进了Lys29-连接和ASK1(凋亡信号调节蛋白1)的激活，并促进病毒感染时I型干扰素的产生。Fbxo21基因缺陷可损害病毒诱导的Lys29连接和ASK1的激活，减弱c-jun氨基末端激酶(JNK)和p38信号通路，减少促炎细胞因子和I型干扰素的产生，从而降低抗病毒天然应答，增强病毒复制。因此，Fbxo21在抗病毒先天免疫反应中需要通过ASK1的Lys29-连接激活ASK1，从而为SCF复合体在先天免疫反应中的非蛋白分解作用提供了机械性的见解。
Protein ubiquitination regulated by ubiquitin ligases plays important roles in innate immunity. However, key regulators of ubiquitination during innate response and roles of new types of ubiquitination (apart from Lys48- and Lys63-linkage) in control of innate signaling have not been clearly understood. Here we report that F-box only protein Fbxo21, a functionally unknown component of SCF (Skp1 Cull F-box protein) complex, facilitates Lys29-linkage and activation of ASK1 (apoptosis signal-regulating kinase 1), and promotes type I interferon production upon viral infection. Fbxo21 deficiency in mice cells impairs virus-induced Lys29-linkage and activation of ASK1, attenuates c-Jun N-terminal kinase (JNK) and p38 signaling pathway, and decreases the production of proinflammatory cytokines and type I interferon, resulting in reduced antiviral innate response and enhanced virus replication. Therefore Fbxo21 is required for ASK1 activation via Lys29-linkage of ASK1 during antiviral innate response, providing mechanistic insights into non-proteolytic roles of SCF complex in innate immune response.