水泡性口炎病毒
基因敲除
泛素连接酶
小干扰RNA
细胞生物学
生物
TLR3型
泛素
钻机-I
免疫沉淀
干扰素调节因子
干扰素
分子生物学
转录因子
核糖核酸
病毒
受体
先天免疫系统
病毒学
基因
Toll样受体
生物化学
作者
Wei Zhao,Limin Wang,Meng Zhang,Peng Wang,Chao Yuan,Jianni Qi,Hong Meng,Chengjiang Gao
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2012-06-01
卷期号:188 (11): 5311-5318
被引量:67
标识
DOI:10.4049/jimmunol.1103506
摘要
Abstract Recognition of RNA virus through TLR and RIG-I–like receptor results in rapid expression of type I IFNs, which play an essential role in host antiviral responses. However, the mechanisms to terminate the production of type I IFNs are not well defined. In the current study, we identified a member of the tripartite motif (TRIM) family, TRIM38, as a negative regulator in TLR3/4- and RIG-I–mediated IFN-β signaling. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of IFN regulatory factor 3 and enhanced expression of IFN-β, whereas overexpression of TRIM38 had opposite effects. Coimmunoprecipitation and colocalization experiments demonstrated that TRIM38 interacted with NF-κB–activating kinase-associated protein 1 (NAP1), which is required for TLR-induced IFN regulatory factor 3 activation and IFN-β production. As an E3 ligase, TRIM38 promoted K48-linked polyubiquitination and proteasomal degradation of NAP1. Thus, knockdown of TRIM38 expression resulted in higher protein level of NAP1 in primary macrophages. Consistent with the inhibitory roles in TLR3/4- and RIG-I–mediated IFN-β signaling, knockdown of TRIM38 significantly inhibited the replication of vesicular stomatitis virus. Overexpression of TRIM38 resulted in enhanced replication of vesicular stomatitis virus. Therefore, our results demonstrate that TRIM38 is a negative regulator for TLR and RIG-I–mediated IFN-β production by targeting NAP1 for ubiquitination and subsequent proteasome-mediated degradation.
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