Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan;
Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan.
J Immunol. 2019 Apr 1;202(7):1942-1947. doi: 10.4049/jimmunol.1801388. Epub 2019 Feb 18.
The NLRP3 inflammasome has important roles in the pathogenesis of various inflammatory diseases. However, the regulatory mechanisms of the NLRP3 inflammasome are not fully understood. In this study, we attempted to identify molecules that interact with NLRP3 upon its activation. We identified G protein subunit β 1 (GNB1), a downstream molecule of G protein-coupled receptors (GPCRs), which regulates the NLRP3 inflammasome activation. GNB1 was physically associated with NLRP3 via the pyrin domain of NLRP3. Activation of the NLRP3 inflammasome was enhanced in GNB1-knockdown or GNB1-deficient murine macrophages, although a lack of GNB1 did not affect activation of the AIM2 inflammasome. ASC oligomerization induced by NLRP3 was enhanced by GNB1 deficiency. Conversely, NLRP3-dependent ASC oligomerization was inhibited by the overexpression of GNB1. This study indicates that GNB1 negatively regulates NLRP3 inflammasome activation by suppressing NLRP3-dependent ASC oligomerization, and it provides a regulatory mechanism of the NLRP3 inflammasome.
NLRP3 炎性小体在各种炎症性疾病的发病机制中具有重要作用。然而，NLRP3 炎性小体的调节机制尚不完全清楚。在本研究中，我们试图鉴定出在 NLRP3 激活时与其相互作用的分子。我们鉴定出 G 蛋白亚基β 1（GNB1），一种 G 蛋白偶联受体（GPCR）的下游分子，可调节 NLRP3 炎性小体的激活。GNB1 通过 NLRP3 的吡咯啉结构域与 NLRP3 发生物理结合。在 GNB1 敲低或 GNB1 缺陷型小鼠巨噬细胞中，NLRP3 炎性小体的激活增强，尽管缺乏 GNB1 并不影响 AIM2 炎性小体的激活。GNB1 缺乏可增强 NLRP3 诱导的 ASC 寡聚化。相反，NLRP3 依赖性 ASC 寡聚化可被 GNB1 的过表达抑制。本研究表明，GNB1 通过抑制 NLRP3 依赖性 ASC 寡聚化来负调控 NLRP3 炎性小体的激活，并为 NLRP3 炎性小体的调节机制提供了依据。
