Another spin at the wheel The NLR (nucleotide-binding domain leucine-rich repeat) proteins are a key intracellular component of the early innate immune response to pathogens. After binding microbial ligands, assorted NLR family members assemble to form enormous signaling complexes (inflammasomes), which promote pro-inflammatory cytokine secretion and cell death. Tenthorey et al. used cryo-electron microscopy to visualize an assembled ligand-bound inflammasome. They find that when NAIP5 binds flagellin, it changes conformation, which triggers a rotation in monomeric NLRC4, catalyzing further NLRC4 recruitment. Steric clash results in a partially open structure, in contrast with previous descriptions of a closed symmetrical “wheel.” Furthermore, NAIP5 recognizes multiple regions of its ligand, and mutations of flagellin that allow for NAIP5 evasion compromise bacterial fitness. Science, this issue p. 888 NLR binding to bacterial flagellin entails the recognition of multiple ligand surfaces, which limits easy microbial evasion. Robust innate immune detection of rapidly evolving pathogens is critical for host defense. Nucleotide-binding domain leucine-rich repeat (NLR) proteins function as cytosolic innate immune sensors in plants and animals. However, the structural basis for ligand-induced NLR activation has so far remained unknown. NAIP5 (NLR family, apoptosis inhibitory protein 5) binds the bacterial protein flagellin and assembles with NLRC4 to form a multiprotein complex called an inflammasome. Here we report the cryo–electron microscopy structure of the assembled ~1.4-megadalton flagellin-NAIP5-NLRC4 inflammasome, revealing how a ligand activates an NLR. Six distinct NAIP5 domains contact multiple conserved regions of flagellin, prying NAIP5 into an open and active conformation. We show that innate immune recognition of multiple ligand surfaces is a generalizable strategy that limits pathogen evolution and immune escape.

中文翻译：

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NAIP5 检测鞭毛蛋白的结构基础：一种限制病原体免疫逃避的策略

车轮上的另一个旋转 NLR（核苷酸结合域富含亮氨酸重复序列）蛋白是对病原体的早期先天免疫反应的关键细胞内成分。结合微生物配体后，各种 NLR 家族成员组装形成巨大的信号复合物（炎性体），促进促炎细胞因子分泌和细胞死亡。Tenthorey 等人。使用冷冻电子显微镜观察组装的配体结合的炎性体。他们发现，当 NAIP5 结合鞭毛蛋白时，它会改变构象，从而触发单体 NLRC4 的旋转，进一步催化 NLRC4 募集。空间碰撞导致部分开放的结构，与之前描述的封闭对称“轮”形成对比。此外，NAIP5 识别其配体的多个区域，允许 NAIP5 逃避的鞭毛蛋白突变会损害细菌适应性。科学，这个问题 p。888 NLR 与细菌鞭毛蛋白的结合需要识别多个配体表面，这限制了容易的微生物逃逸。对快速进化的病原体进行强大的先天免疫检测对于宿主防御至关重要。核苷酸结合域富含亮氨酸重复 (NLR) 蛋白在植物和动物中充当细胞溶质先天免疫传感器。然而，迄今为止，配体诱导的 NLR 激活的结构基础仍然未知。NAIP5（NLR 家族，细胞凋亡抑制蛋白 5）结合细菌蛋白鞭毛蛋白并与 NLRC4 组装形成称为炎性体的多蛋白复合物。在这里，我们报告了组装的 ~1.4 兆道尔顿鞭毛蛋白-NAIP5-NLRC4 炎症小体的冷冻电子显微镜结构，揭示配体如何激活 NLR。六个不同的 NAIP5 结构域接触鞭毛蛋白的多个保守区域，将 NAIP5 撬入开放和活跃的构象。我们表明，多配体表面的先天免疫识别是一种可推广的策略，可限制病原体进化和免疫逃逸。