College of Life Sciences, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang University, Hangzhou 310058, People's Republic of China; and.
College of Life Sciences, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang University, Hangzhou 310058, People's Republic of China; and
J Immunol. 2018 Oct 1;201(7):1946-1966. doi: 10.4049/jimmunol.1800498. Epub 2018 Aug 27.
NLRP1 inflammasome is one of the best-characterized inflammasomes in humans and other mammals. However, the existence of this inflammasome in nonmammalian species remains poorly understood. In this study, we report the molecular and functional identification of an NLRP1 homolog, NLRP1 (NLRP1) from a zebrafish () model. This NLRP1 possesses similar structural architecture to mammalian NLRP1s. It can trigger the formation of a classical inflammasome for the activation of zebrafish inflammatory caspases ( Caspase [Caspase]-A and Caspase-B) and maturation of IL-1β in a ASC (ASC)-dependent manner. In this process, NLRP1 promotes the aggregation of ASC into a filament with ASC core and ASC cluster. The assembly of NLRP1 inflammasome depends on the CARD-CARD homotypic interaction between NLRP1 and ASC core, and PYD-PYD interaction between Caspase-A/B and ASC cluster. The FIIND domain in NLRP1 is necessary for inflammasome assembly. To understand the mechanism of how the two Caspases are coordinated in NLRP1 inflammasome, we propose a two-step sequential activation model. In this model, the recruitment and activation of Caspase-A/B in the inflammasome is shown in an alternate manner, with a preference for Caspase-A followed by a subsequent selection for Caspase-B. By using morpholino oligonucleotide-based knockdown assays, the NLRP1 inflammasome was verified to play important functional roles in antibacterial innate immunity in vivo. These observations demonstrate that the NLRP1 inflammasome originated as early as in teleost fish. This finding not only gives insights into the evolutionary history of inflammasomes but also provides a favorable animal model for the study of NLRP1 inflammasome-mediated immunology and diseases.
NLRP1 炎性小体是人类和其他哺乳动物中研究最为透彻的炎性小体之一。然而，该炎性小体在非哺乳动物物种中的存在仍知之甚少。在本研究中，我们报道了一种来自斑马鱼（Danio rerio）模型的 NLRP1 同源物 NLRP1（NLRP1）的分子和功能鉴定。该 NLRP1 具有与哺乳动物 NLRP1s 相似的结构架构。它可以触发经典炎性小体的形成，从而激活斑马鱼炎症半胱天冬酶（Caspase）-A 和 Caspase-B，并以 ASC 依赖性方式成熟白细胞介素-1β（IL-1β）。在此过程中，NLRP1 促进 ASC 形成具有 ASC 核心和 ASC 簇的丝状结构。NLRP1 炎性小体的组装依赖于 NLRP1 和 ASC 核心之间的 CARD-CARD 同源相互作用，以及 Caspase-A/B 和 ASC 簇之间的 PYD-PYD 相互作用。NLRP1 中的 FIIND 结构域对于炎性小体组装是必需的。为了了解两个 Caspase 在 NLRP1 炎性小体中如何协调的机制，我们提出了两步连续激活模型。在该模型中，炎性小体中 Caspase-A/B 的募集和激活以交替方式进行，优先选择 Caspase-A，然后随后选择 Caspase-B。通过使用基于 morpholino 寡核苷酸的敲低测定，验证 NLRP1 炎性小体在体内抗菌先天免疫中发挥重要功能作用。这些观察结果表明，NLRP1 炎性小体早在硬骨鱼中就已经出现。这一发现不仅深入了解了炎性小体的进化历史，而且为 NLRP1 炎性小体介导的免疫学和疾病研究提供了一个有利的动物模型。
