PDF(Pubmed)
Abstract：
NLRP1 is an innate immune receptor that detects pathogen-associated signals, assembles into a multiprotein structure called an inflammasome, and triggers a proinflammatory form of cell death called pyroptosis. We previously discovered that the oxidized, but not the reduced, form of thioredoxin-1 directly binds to NLRP1 and represses inflammasome formation. However, the molecular basis for NLRP1\'s selective association with only the oxidized form of TRX1 has not yet been established. Here, we leveraged AlphaFold-Multimer, site-directed mutagenesis, thiol-trapping experiments, and mass spectrometry to reveal that a specific cysteine residue (C427 in humans) on NLRP1 forms a transient disulfide bond with oxidized TRX1. Overall, this work demonstrates how NLRP1 monitors the cellular redox state, further illuminating an unexpected connection between the intracellular redox potential and the innate immune system.
摘要：
NLRP1是一种先天免疫受体，可检测病原体相关信号，组装成一种称为炎性体的多蛋白结构，并引发一种称为焦亡的促炎细胞死亡。我们以前发现氧化的，但不是减少的，硫氧还蛋白-1的形式直接与NLRP1结合并抑制炎症小体的形成。然而,NLRP1仅与TRX1的氧化形式选择性缔合的分子基础尚未确定。这里,我们利用AlphaFold-Multimer,定点诱变，硫醇捕集实验，和质谱显示NLRP1上的特定半胱氨酸残基（人类中的C427）与氧化的TRX1形成瞬时二硫键。总的来说,这项工作展示了NLRP1如何监测细胞氧化还原状态，进一步阐明了细胞内氧化还原电位和先天免疫系统之间的意想不到的联系。
