Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6
Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6
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病毒感染诱导 USP25 通过介导 TRAF3 和 TRAF6 的稳定来促进先天抗病毒反应
DOI：
10.1073/pnas.1509968112
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发表时间：
2015-09-08
影响因子：
11.1
通讯作者：
Zhong, Bo
中科院分区：
文献类型：
--
作者：
Lin, Dandan;Zhang, Man;Zhong, Bo
宿主病原体识别受体检测入侵病毒的核酸，并启动一系列信号传导途径，从而产生 I 型干扰素 (IFN) 和促炎细胞因子。在这里，我们发现病毒感染诱导的去泛素酶 (DUB)、泛素特异性蛋白酶 25 (USP25) 是宿主防御 RNA 和 DNA 病毒所必需的。 RNA或DNA病毒感染后，与野生型细胞相比，Usp25(-/-)细胞中转录因子IRF3和NF-κB的激活受损，I型干扰素和促炎细胞因子的产生受到抑制。一致地，与野生型小鼠相比，USP25 缺陷小鼠更容易受到 H5N1 或 HSV-1 感染。 USP25在RNA或DNA病毒感染后与TRAF3和TRAF6相关，并分别保护病毒诱导的蛋白酶体依赖性或独立的TRAF3和TRAF6降解。此外，将TRAF3和TRAF6重建到Usp25(-/-) MEF中可以恢复病毒触发的I型干扰素和促炎细胞因子的产生。因此，我们的研究结果揭示了之前发现的 USP25 对 RNA 和 DNA 病毒先天免疫反应的正反馈调节。
Host pathogen-recognition receptors detect nucleic acid from invading viruses and initiate a series of signaling pathways that lead to the production of type I interferons (IFNs) and proinflammatory cytokines. Here, we found that a viral infection-induced deubiquitinase (DUB), ubiquitin-specific protease 25 (USP25) was required for host defense against RNA and DNA viruses. The activation of transcription factors IRF3 and NF-kappa B was impaired and the production of type I IFNs and proinflammatory cytokines was inhibited in Usp25(-/-) cells compared with the wild-type counterparts after RNA or DNA viruses infection. Consistently, USP25 deficient mice were more susceptible to H5N1 or HSV-1 infection compared with the wild-type mice. USP25 was associated with TRAF3 and TRAF6 after infection by RNA or DNA viruses and protected virus-induced proteasome-dependent or independent degradation of TRAF3 and TRAF6, respectively. Moreover, reconstitution of TRAF3 and TRAF6 into Usp25(-/-) MEFs restored virus-triggered production of type I IFNs and proinflammatory cytokines. Our findings thus reveal a previously uncovered positive feedback regulation of innate immune responses against RNA and DNA viruses by USP25.