The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting in NLRP3 inflammasome activation. DL-all-rac-α-tocopherol, a synthetic form of vitamin E, inhibited the Lamtor1–HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. Further, DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. These results provide novel insights into the role of lysosomes in the activation of NLRP3 inflammasomes by the Ragulator complex.

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溶酶体 Ragulator 复合物通过 HDAC6 激活体内 NLRP3 炎症小体

NLRP3 炎症小体的细胞激活是由各种细胞器在时空上协调的，但溶酶体是否参与这一过程仍不清楚。在这里，我们展示了溶酶体膜束缚的 Ragulator 复合物在 NLRP3 炎症小体激活中的重要作用。Lamtor1（Ragulator 复合物的重要组成部分）的缺陷会消除小鼠巨噬细胞和人类单核细胞中 NLRP3 炎性体的激活。骨髓特异性 Lamtor1 缺陷小鼠表现出 NLRP3 相关炎症疾病严重程度的显着减弱，包括 LPS 诱导的败血症、明矾诱导的腹膜炎和尿酸钠 (MSU) 诱导的关节炎。从机制上讲，Lamtor1 与 NLRP3 和组蛋白脱乙酰酶 6 (HDAC6) 相互作用。HDAC6 增强 Lamtor1 和 NLRP3 之间的相互作用，导致 NLRP3 炎性体激活。DL-all-rac-α-生育酚是维生素 E 的合成形式，可抑制 Lamtor1-HDAC6 相互作用，导致 NLRP3 炎性体激活减少。此外，DL-all-rac-α-生育酚可缓解急性痛风性关节炎和密歇根州立大学诱发的腹膜炎。这些结果为溶酶体在 Ragulator 复合物激活 NLRP3 炎症小体中的作用提供了新的见解。