Proper regulation of cellular response to environmental stress is crucial for maintaining biological homeostasis and is achieved by the balance between cell death processes, such as the formation of the pyroptosis-inducing NLRP3 inflammasome, and pro-survival processes, such as stress granule (SG) assembly. However, the functional interplay between these two stress-responsive organelles remains elusive. Here, we identified DHX33, a viral RNA sensor for the NLRP3 inflammasome, as a SG component, and the SG-nucleating protein G3BP as an NLRP3 inflammasome component. We also found that a decrease in intracellular potassium (K+) concentration, a key common step in NLRP3 inflammasome activation, markedly inhibited SG assembly. Therefore, when macrophages are exposed to stress stimuli with the potential to induce both SGs and the NLRP3 inflammasome, such as cytoplasmic poly(I:C) stimulation, they preferentially form the NLRP3 inflammasome but avoid SG assembly by sequestering G3BP into the inflammasome and by inducing a reduction in intracellular K+ levels. Thus, under such conditions, DHX33 is primarily utilized as a viral RNA sensor for the inflammasome. Our data reveal the functional crosstalk between NLRP3 inflammasome-mediated pyroptosis and SG-mediated cell survival pathways, and delineate a molecular mechanism that regulates cell-fate decisions and anti-viral innate immunity under stress.

中文翻译：

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NLRP3 炎症小体的形成通过多种机制抑制应激颗粒组装

细胞对环境应激反应的适当调节对于维持生物体内平衡至关重要，并且是通过细胞死亡过程（例如诱导焦亡的 NLRP3 炎症小体的形成）和促生存过程（例如应激颗粒 (SG)）之间的平衡来实现的集会。然而，这两种应激反应细胞器之间的功能相互作用仍然难以捉摸。在这里，我们将 NLRP3 炎症小体的病毒 RNA 传感器 DHX33 确定为 SG 成分，并将 SG 成核蛋白 G3BP 鉴定为 NLRP3 炎症小体成分。我们还发现，细胞内钾 (K+) 浓度的降低（NLRP3 炎性体激活的关键共同步骤）显着抑制 SG 组装。因此，当巨噬细胞受到可能诱导 SG 和 NLRP3 炎症小体的应激刺激（例如细胞质 Poly(I:C) 刺激）时，它们会优先形成 NLRP3 炎症小体，但通过将 G3BP 隔离到炎症小体中来避免 SG 组装，并通过诱导细胞内 K+ 水平降低。因此，在这种条件下，DHX33 主要用作炎性体的病毒 RNA 传感器。我们的数据揭示了 NLRP3 炎症小体介导的细胞焦亡和 SG 介导的细胞存活途径之间的功能串扰，并描绘了在压力下调节细胞命运决定和抗病毒先天免疫的分子机制。