Diverse viral proteases activate the NLRP1 inflammasome.
Diverse viral proteases activate the NLRP1 inflammasome.
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多种病毒蛋白酶激活NLRP1炎症体。
DOI：
10.7554/elife.60609
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发表时间：
2021-01-07
期刊：
影响因子：
7.7
通讯作者：
Daugherty MD
中科院分区：
文献类型：
--
作者：
Tsu BV;Beierschmitt C;Ryan AP;Agarwal R;Mitchell PS;Daugherty MD
NLRP1炎性小体是一种多蛋白复合物，是一种有效的炎症激活剂。小鼠NLRP1B可被细菌致死毒素（LeTx）蛋白酶通过蛋白水解裂解激活，导致NLRP1B的n端结构域降解，并释放生物活性的c端结构域，其中包括caspase激活和募集结构域（CARD）。然而，能够激活人类NLRP1的天然病原体衍生效应物仍然未知。在这里，我们使用进化模型来鉴定来自不同小核糖核酸病毒的几种蛋白酶，这些蛋白酶在蛋白质的快速进化区域内切割人类NLRP1，导致NLRP1炎性体的宿主特异性和病毒特异性激活。我们的研究表明，NLRP1作为一种“触网”来识别多种病毒蛋白酶的酶促功能，并表明宿主对病毒多蛋白裂解位点的模仿可能是激活强大的炎症免疫反应的一种进化策略。免疫系统识别致病微生物，如细菌和病毒，并在它们造成伤害之前将它们从体内清除。当免疫系统第一次检测到这些外来入侵者时，一个被称为炎性体的多部分结构就会启动炎症反应，帮助对抗微生物。几种传感器蛋白可以激活炎性小体，包括一种名为NLRP1B的小鼠。这种蛋白质已经进化出一个可以被细菌毒素切割的特殊部位。一旦被切割，这个区域就像一个生物触网，激发NLRP1B的作用，允许传感器激活炎性体系统。人类有一种类似的蛋白质，叫做NLRP1，但目前还不清楚这种蛋白质是否也进化出了一个可以感知微生物蛋白质的绊线区域。为了回答这个问题，Tsu、Beierschmitt等人开始研究NLRP1是否可以被小核糖核酸病毒科的病毒激活，小核糖核酸病毒科是脊髓灰质炎、甲型肝炎和普通感冒等疾病的病因。这表明NLRP1含有一个切割位点，用于小核糖核酸病毒家族中一些病毒（但不是全部）产生的酶。进一步的实验证实，当小核糖核酸病毒酶在病毒感染期间穿过该区域时，它会触发NLRP1激活炎性体并启动免疫反应。来自不同病毒的酶也被发现在不同的位点切割人类NLRP1，并且该蛋白对切割的敏感性在不同的动物物种之间有所不同。例如，Tsu， Beierschmitt等人发现小鼠的NLRP1B也能够感知小核糖核酸病毒，不同的酶在不同程度上激活和切割NLRP1B和NLRP1：这影响了这两种蛋白对特定病毒感染的感知能力。这种变异表明，在病毒蛋白和免疫系统之间存在着一场正在进行的进化军备竞赛：随着病毒蛋白的变化和新蛋白的出现，NLRP1迅速进化出新的“触网”位点，使其能够感知感染并启动炎症反应。当NLRP1B在病毒感染期间激活炎性体时会发生什么仍然是一个悬而未决的问题。发现小鼠NLRP1B与人类NLRP1具有相同的特征，可以开发动物模型来研究tripwire在抗病毒防御和与某些病毒感染相关的过度活跃炎症中的作用。了解激活NLRP1炎性体的病毒类型，以及由此产生的免疫反应的结果，可能对病毒感染的未来治疗有意义。
The NLRP1 inflammasome is a multiprotein complex that is a potent activator of inflammation. Mouse NLRP1B can be activated through proteolytic cleavage by the bacterial Lethal Toxin (LeTx) protease, resulting in degradation of the N-terminal domains of NLRP1B and liberation of the bioactive C-terminal domain, which includes the caspase activation and recruitment domain (CARD). However, natural pathogen-derived effectors that can activate human NLRP1 have remained unknown. Here, we use an evolutionary model to identify several proteases from diverse picornaviruses that cleave human NLRP1 within a rapidly evolving region of the protein, leading to host-specific and virus-specific activation of the NLRP1 inflammasome. Our work demonstrates that NLRP1 acts as a 'tripwire' to recognize the enzymatic function of a wide range of viral proteases and suggests that host mimicry of viral polyprotein cleavage sites can be an evolutionary strategy to activate a robust inflammatory immune response. The immune system recognizes disease-causing microbes, such as bacteria and viruses, and removes them from the body before they can cause harm. When the immune system first detects these foreign invaders, a multi-part structure known as the inflammasome launches an inflammatory response to help fight the microbes off. Several sensor proteins can activate the inflammasome, including one in mice called NLRP1B. This protein has evolved a specialized site that can be cut by a bacterial toxin. Once cleaved, this region acts like a biological tripwire and sparks NLRP1B into action, allowing the sensor to activate the inflammasome system. Humans have a similar protein called NLRP1, but it is unclear whether this protein has also evolved a tripwire region that can sense microbial proteins. To answer this question, Tsu, Beierschmitt et al. set out to find whether NLRP1 can be activated by viruses in the Picornaviridae family, which are responsible for diseases like polio, hepatitis A, and the common cold. This revealed that NLRP1 contains a cleavage site for enzymes produced by some, but not all, of the viruses in the picornavirus family. Further experiments confirmed that when a picornavirus enzyme cuts through this region during a viral infection, it triggers NLRP1 to activate the inflammasome and initiate an immune response. The enzymes from different viruses were also found to cleave human NLRP1 at different sites, and the protein’s susceptibility to cleavage varied between different animal species. For instance, Tsu, Beierschmitt et al. discovered that NLRP1B in mice is also able to sense picornaviruses, and that different enzymes activate and cleave NLRP1B and NLRP1 to varying degrees: this affected how well the two proteins are expected to be able to sense specific viral infections. This variation suggests that there is an ongoing evolutionary arms-race between viral proteins and the immune system: as viral proteins change and new ones emerge, NLRP1 rapidly evolves new tripwire sites that allow it to sense the infection and launch an inflammatory response. What happens when NLRP1B activates the inflammasome during a viral infection is still an open question. The discovery that mouse NLRP1B shares features with human NLRP1 could allow the development of animal models to study the role of the tripwire in antiviral defenses and the overactive inflammation associated with some viral infections. Understanding the types of viruses that activate the NLRP1 inflammasome, and the outcomes of the resulting immune response, may have implications for future treatments of viral infections.