Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Cell. 2014 Mar 13;156(6):1193-1206. doi: 10.1016/j.cell.2014.02.008.
Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PAPERFLICK:
炎性小体通过激活半胱天冬酶-1 促进细胞因子成熟和细胞死亡，从而在细胞内引发宿主防御。AIM2 和 NLRP3 是两种主要炎性小体家族中的代表性传感器蛋白。衔接蛋白 ASC 通过传感器蛋白和半胱天冬酶-1 之间的吡啶结构域（PYD）相互作用以及 ASC 和半胱天冬酶-1 之间的半胱氨酸天冬氨酸蛋白酶激活和募集结构域（CARD）相互作用来桥接传感器蛋白和半胱天冬酶-1，从而形成三元炎性小体复合物。我们发现 PYD 和 CARD 均形成纤维。活化的 AIM2 和 NLRP3 引发 ASC 的 PYD 纤维，继而聚集 ASC 的 CARD。因此，ASC 引发半胱天冬酶-1 的 CARD 纤维，导致接近诱导激活。内源性 NLRP3 炎性小体也是纤维状的。在接近原子分辨率的 ASC(PYD)纤维的冷冻电子显微镜结构为同源和异源 PYD/PYD 缔合提供了模板，这一点得到了结构指导的突变分析的证实。我们提出，两种家族的 ASC 依赖性炎性小体具有统一的组装机制，该机制涉及两个连续的引发聚合步骤。
