A promiscuous inflammasome sparks replication of a common tumor virus
A promiscuous inflammasome sparks replication of a common tumor virus
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DOI：
10.1073/pnas.1919133117
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发表时间：
2020-01-21
影响因子：
11.1
通讯作者：
Bhaduri-McIntosh, Sumita
中科院分区：
文献类型：
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作者：
Burton, Eric M.;Goldbach-Mansky, Raphaela;Bhaduri-McIntosh, Sumita
病毒会激活炎性小体，但随后会破坏由此产生的炎症反应，以避免消除。我们询问病毒是否可以使用这种被激活或启动的炎性小体来直接帮助它们的繁殖和传播。由于疱疹病毒是调节细胞功能的专家，我们调查了EB病毒(EBV)是否利用炎性小体来激活其复制或裂解阶段。事实上，我们的实验表明，EBV利用几个炎症体传感器来实际上激活其从静止/潜伏的复制阶段。特别是，TXNIP是一个关键的炎症体中介，导致NLRP3炎症体的组装，导致caspase-1介导的异染色质诱导的表观遗传抑制子KAP1/TRIM28在一群细胞中耗尽。结果，只有TXNIP(Hi)KAP1(Lo)细胞，即处于启动/裂解状态的TXNIP(Hi)KAP1(Lo)细胞，开启复制/裂解/再激活开关蛋白的表达以进入复制阶段。我们的发现1)表明EBV的逃逸策略与关键的细胞危险感知机制相吻合，2)表明转录可能受到KAP1丰度的调节，而不是通过其翻译后修饰进行规范调节，3)机制上将糖尿病与肿瘤病毒的解除调节联系在一起，糖尿病经常激活NLRP3炎症体，以及4)来自NOMID(新生儿发病的多系统炎症性疾病)患者的B淋巴细胞具有NLRP3突变和过度活跃的先天反应，在控制疱疹病毒方面存在缺陷。
Viruses activate inflammasomes but then subvert resulting inflammatory responses to avoid elimination. We asked whether viruses could instead use such activated or primed inflammasomes to directly aid their propagation and spread. Since herpesviruses are experts at coopting cellular functions, we investigated whether Epstein-Barr virus (EBV), an oncoherpesvirus, exploits inflammasomes to activate its replicative or lytic phase. Indeed, our experiments reveal that EBV exploits several inflammasome sensors to actually activate its replicative phase from quiescence/latency. In particular, TXNIP, a key inflammasome intermediary, causes assembly of the NLRP3 inflammasome, resulting in caspase-1-mediated depletion of the heterochromatin-inducing epigenetic repressor KAP1/TRIM28 in a subpopulation of cells. As a result, only TXNIP(hi)KAP1(lo) cells, that is, in a primed/prolytic state, turn expression of the replication/lytic/reactivation switch protein on to enter the replicative phase. Our findings 1) demonstrate that EBV dovetails its escape strategy to a key cellular danger-sensing mechanism, 2) indicate that transcription may be regulated by KAP1 abundance aside from canonical regulation through its posttranslational modification, 3) mechanistically link diabetes, which frequently activates the NLRP3 inflammasome, to deregulation of a tumor virus, and 4) demonstrate that B lymphocytes from NOMID (neonatal onset multi-system inflammatory disease) patients who have NLRP3 mutations and suffer from hyperactive innate responses are defective in controlling a herpesvirus.