Ubiquitin-Specific Protease 2b Negatively Regulates IFN-β Production and Antiviral Activity by Targeting TANK-Binding Kinase 1
Ubiquitin-Specific Protease 2b Negatively Regulates IFN-β Production and Antiviral Activity by Targeting TANK-Binding Kinase 1
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DOI：
10.4049/jimmunol.1302634
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发表时间：
2014-09
期刊：
影响因子：
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通讯作者：
Lei Zhang;Xueying Zhao;Meng Zhang;Wei Zhao;Chengjiang Gao
中科院分区：
文献类型：
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作者：
Lei Zhang;Xueying Zhao;Meng Zhang;Wei Zhao;Chengjiang Gao
TANK 结合激酶 1 (TBK1) 对于各种先天受体下游的 IFN 调节因子 3 激活和 IFN-β 产生至关重要。然而，TBK1 激活如何终止尚不清楚。在这项研究中，我们发现泛素特异性蛋白酶 (USP) 2b 是 TBK1 激活的新负调节因子。 USP2b 的过度表达抑制视黄酸诱导基因 I 介导的 IFN-β 信号传导；相反，通过小干扰RNA敲低USP2b表达增强了视黄酸诱导基因-I介导的IFN-β信号传导。免疫共沉淀实验证明 USP2b 与 TBK1 相互作用。作为一种去泛素化酶，USP2b 被证明可以从 TBK1 上裂解 K63 连接的多聚泛素链，从而抑制 TBK1 激酶活性。与USP2b对TBK1激活的抑制作用一致，USP2b的敲低显着抑制水泡性口炎病毒的复制，而USP2b的过表达导致水泡性口炎病毒的复制增强。因此，我们的研究结果表明，USP2b 使 TBK1 中 K63 连接的多聚泛素链去泛素化，从而终止 TBK1 激活并负向调节 IFN-β 信号传导和抗病毒免疫反应。
TANK-binding kinase 1 (TBK1) is essential for IFN regulatory factor 3 activation and IFN-β production downstream of various innate receptors. However, how TBK1 activation is terminated is not well defined. In this study, we identified ubiquitin-specific protease (USP) 2b as a new negative regulator for TBK1 activation. Overexpression of USP2b inhibited retinoic acid–inducible gene-I–mediated IFN-β signaling; in contrast, knockdown of USP2b expression by small interfering RNA enhanced retinoic acid–inducible gene-I–mediated IFN-β signaling. Coimmunoprecipitation experiments demonstrated that USP2b interacted with TBK1. As a deubiquitinating enzyme, USP2b was demonstrated to cleave K63-linked polyubiquitin chains from TBK1 to inhibit TBK1 kinase activity. Consistent with the inhibitory roles of USP2b on TBK1 activation, knockdown of USP2b significantly inhibited the replication of vesicular stomatitis virus, whereas overexpression of USP2b resulted in enhanced replication of vesicular stomatitis virus. Therefore, our findings demonstrated that USP2b deubiquitinates K63-linked polyubiquitin chains from TBK1 to terminate TBK1 activation and negatively regulate IFN-β signaling and antiviral immune response.