The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25.
The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25.
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泛素特异性蛋白酶 USP15 通过去泛素化 TRIM25 来促进 RIG-I 介导的抗病毒信号传导。
DOI：
10.1126/scisignal.2004577
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发表时间：
2014-01-07
影响因子：
7.3
通讯作者：
Gack MU
中科院分区：
文献类型：
--
作者：
Pauli EK;Chan YK;Davis ME;Gableske S;Wang MK;Feister KF;Gack MU
泛素化是调节针对病毒感染的先天免疫应答的重要机制。通过泛素E3连接酶三联基序蛋白25（TRIM 25）将赖氨酸63（Lys 63）连接的泛素链连接至RNA传感器视黄酸诱导基因-I（RIG-I），导致RIG-I的活化并刺激抗病毒细胞因子干扰素-α（IFN-α）和IFN-β的产生。相反，线性泛素组装复合物（LUBAC）对TRIM 25的Lys 48连接的泛素化刺激TRIM 25的蛋白酶体降解，从而抑制RIG-I信号传导途径。在这里，我们报告了泛素特异性蛋白酶15（USP 15）去泛素化TRIM 25，防止TRIM 25的LUBAC依赖性降解。通过蛋白纯化和质谱分析，我们确定USP 15是TRIM 25在人类细胞中的相互作用伴侣。通过特异性小干扰RNA敲低内源性USP 15显著增强TRIM 25的泛素化。相比之下，野生型USP 15的表达，而不是其催化失活突变体，减少了TRIM 25的Lys 48连接的泛素化，导致其稳定。此外，USP 15的异位表达增强了I型IFN的TRIM 25和RIG-I依赖性产生，并抑制RNA病毒复制。相反，USP 15的缺失导致IFN产生减少和病毒复制显著增强。总之，这些数据将USP 15鉴定为TRIM 25和RIG-I介导的抗病毒免疫应答的关键调节剂，从而突出了先天免疫信号传导的复杂调节。
Ubiquitylation is an important mechanism for regulating innate immune responses to viral infections. Attachment of lysine 63 (Lys63)–linked ubiquitin chains to the RNA sensor retinoic acid–inducible gene-I (RIG-I) by the ubiquitin E3 ligase tripartite motif protein 25 (TRIM25) leads to the activation of RIG-I and stimulates production of the antiviral cytokines interferon-α (IFN-α) and IFN-β. Conversely, Lys48-linked ubiquitylation of TRIM25 by the linear ubiquitin assembly complex (LUBAC) stimulates the proteasomal degradation of TRIM25, thereby inhibiting the RIG-I signaling pathway. Here, we report that ubiquitin-specific protease 15 (USP15) deubiquitylates TRIM25, preventing the LUBAC-dependent degradation of TRIM25. Through protein purification and mass spectrometry analysis, we identified USP15 as an interaction partner of TRIM25 in human cells. Knockdown of endogenous USP15 by specific small interfering RNA markedly enhanced the ubiquitylation of TRIM25. In contrast, expression of wild-type USP15, but not its catalytically inactive mutant, reduced the Lys48-linked ubiquitylation of TRIM25, leading to its stabilization. Furthermore, ectopic expression of USP15 enhanced the TRIM25- and RIG-I–dependent production of type I IFN and suppressed RNA virus replication. In contrast, depletion of USP15 resulted in decreased IFN production and markedly enhanced viral replication. Together, these data identify USP15 as a critical regulator of the TRIM25- and RIG-I–mediated antiviral immune response, thereby highlighting the intricate regulation of innate immune signaling.
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DOI：
10.1074/jbc.m109.089912
发表时间：
2010-06-25
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Nistal-Villán E;Gack MU;Martínez-Delgado G;Maharaj NP;Inn KS;Yang H;Wang R;Aggarwal AK;Jung JU;García-Sastre A
通讯作者：
García-Sastre A
影响因子：
16
作者：
Inn KS;Gack MU;Tokunaga F;Shi M;Wong LY;Iwai K;Jung JU
通讯作者：
Jung JU
影响因子：
5.6
作者：
Huang, Xiaohua;Langelotz, Corinna;Dubiel, Wolfgang
通讯作者：
Dubiel, Wolfgang
影响因子：
56.9
作者：
Pichlmair, Andreas;Schulz, Oliver;Sousa, Caetano Reis E.
通讯作者：
Sousa, Caetano Reis E.
影响因子：
7.7
作者：
Friedman, Constantin S.;O'Donnell, Marie Anne;Ting, Adrian T.
通讯作者：
Ting, Adrian T.