Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8583, Japan.
J Biochem. 2024 May 31;175(6):629-641. doi: 10.1093/jb/mvae009.
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.
适当调节细胞对环境应激的反应对于维持生物体内平衡至关重要，这是通过细胞死亡过程（如形成诱导细胞焦亡的 NLRP3 炎性小体）和生存过程（如应激颗粒 (SG) 组装）之间的平衡来实现的。然而，这两个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，我们鉴定出 DHX33 是 NLRP3 炎性小体的病毒 RNA 传感器，是 SG 的组成部分，而 SG 成核蛋白 G3BP 是 NLRP3 炎性小体的组成部分。我们还发现，细胞内钾 (K+) 浓度的降低（NLRP3 炎性小体激活的一个关键“共同”步骤）显著抑制了 SG 的组装。因此，当巨噬细胞暴露于可能诱导 SG 和 NLRP3 炎性小体形成的应激刺激物（如细胞质 poly(I:C) 刺激）时，它们通过将 G3BP 隔离到炎性小体中和诱导细胞内 K+ 水平降低，优先形成 NLRP3 炎性小体，但避免 SG 组装。因此，在这种情况下，DHX33 主要被用作炎性小体的病毒 RNA 传感器。我们的数据揭示了 NLRP3 炎性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，并阐明了一种分子机制，该机制调节应激下的细胞命运决定和抗病毒先天免疫。
