Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation.
Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation.
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DOI：
10.1371/journal.ppat.1003506
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Kung HJ
中科院分区：
文献类型：
--
作者：
Izumiya Y;Kobayashi K;Kim KY;Pochampalli M;Izumiya C;Shevchenko B;Wang DH;Huerta SB;Martinez A;Campbell M;Kung HJ
小泛素样修饰物（SUMO）是一种通过将SUMO部分共价连接到多种靶蛋白上来调节多种细胞过程的蛋白质。类小泛素化在许多病毒的复制中也起着重要作用。以前，我们发现卡波西肉瘤相关疱疹病毒（KSHV）编码SUMO连接酶，K-bZIP，催化宿主和病毒蛋白的SUMO化。我们在这里报告说，这种病毒还编码一个基因，作为一个SUMO靶向泛素连接酶（STUbL），优先靶向sumoylated蛋白降解的功能。K-Rta是开启整个裂解周期的主要转录因子，最近发现其对一组选定的底物具有泛素连接酶活性。我们在这项研究中表明，K-Rta包含多个西姆斯（SUMO相互作用基序），并结合SUMO与SUMO多聚体的亲和力更高。像RNF 4一样，原型细胞STUbL，K-Rta降解SUMO-2/3和SUMO-2/3修饰的蛋白质，包括早幼粒细胞白血病（PML）和K-bZIP。PML-NB（核体）或ND-10是类小泛素化蛋白的储存仓库，作为内在免疫应答的一部分，类小泛素化蛋白负调节疱疹病毒感染。疱疹病毒已经进化出不同的方式来降解或分散PML体，KSHV利用K-Rta来抑制PML-NB的形成。这个过程取决于K-Rta结合SUMO的能力，因为K-Rta SIM突变体不能有效降解PML。K-Rta环指样结构域或SIM中的突变在报告基因测定和病毒再激活过程中显著抑制K-Rta反式激活活性。最后，在K-Rta的环指样结构域或SIM中发生突变的KSHV在培养物中复制较差，这表明减少宿主细胞中的SUMO结合物对于病毒复制很重要。据我们所知，这是第一个编码SUMO连接酶和SUMO靶向泛素连接酶的病毒，它们可以一起产生独特的基因调控程序。SUMO（小泛蛋白样修饰剂）对蛋白质的修饰，如磷酸化，现在被认为是几乎所有细胞过程中涉及的重要生化信号。毫不奇怪，它也与病毒复制和宿主免疫反应有关。病毒和宿主蛋白上SUMO信号的及时开启和关闭对于病毒促进其复制是重要的。我们先前描述了识别卡波西肉瘤相关疱疹病毒（KSHV）编码的病毒SUMO E3连接酶，该酶将SUMO与受体蛋白偶联。在这里，我们报告发现了一个SUMO靶向E3泛素连接酶（STUbL）样功能，也由这种病毒编码。K-Rta优先降解sumoylated蛋白，如PML（早幼粒细胞白血病），其负调节病毒复制。KSHV K-Rta被公认为是一种强转录因子和病毒再活化的触发因子。在还原细胞SUMO缀合物方面有缺陷的重组KSHV在其再活化活性方面显著受损。我们的发现不仅揭示了一个新的功能的转录因子，K-Rta，但也指出了动态调节的SUMO环境中疱疹病毒复制的重要性。
The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rta's ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene regulatory programs. Protein modification by SUMO (small ubiquitin-like modifier), like phosphorylation, is now considered to be an important biochemical signal involved in nearly all cellular processes. Not surprisingly, it is also implicated in viral replication and host immune response. Timely turning on and off of SUMO signaling on viral and host proteins are important for virus to advance its replication. We previously described the identification of a viral SUMO E3 ligase encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), which couples SUMO to recipient proteins. Here we report the discovery of a SUMO-targeting E3 ubiquitin ligase (STUbL) like function, also encoded by this virus. K-Rta preferentially degrades sumoylated proteins such as PML (promyelocytic leukemia) which negatively regulates viral replication. KSHV K-Rta is well recognized as a strong transcriptional factor and a trigger for viral reactivation. Recombinant KSHVs defective in reducing cellular SUMO conjugates are significantly compromised in their reactivation activity. Our finding not only uncovers a novel function of the transcriptional factor, K-Rta, but also points to the importance of dynamic regulation of the SUMO environment in herpesvirus replication.
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影响因子：
10.5
作者：
Drane, Pascal;Ouararhni, Khalid;Hamiche, Ali
通讯作者：
Hamiche, Ali
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影响因子：
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影响因子：
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影响因子：
6.7
作者：
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