The Ragulator complex regulates NLRP3 inflammasome activation through interaction with HDAC6

The activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but the precise roles of lysosomes are still unclear. Here we show the vital role of the Ragulator complex, a lysosomal protein, in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophage and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed remarkable attenuation of the severity of NLRP3-associated inflammatory diseases, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with histone deacetylase 6 (HDAC6) during NLRP3 inflammasome activation, and this interaction augmented the interaction between the Ragulator complex and NLRP3. Lack of HDAC6 attenuated the interaction between Lamtor1 and NLRP3, resulting in insufficient NLRP3 inflammasome activation. Furthermore, DL-all-rac-α-tocopherol inhibited Lamtor1–HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. Our results provide insight into the role of lysosomes in providing a platform for the activation of NLRP3 inflammasomes by the Ragulator complex.

NLRP3炎症小体（NLRP3 inflammasome）的激活受多种细胞器的时空调控，但溶酶体（lysosomes）的确切作用仍未明确。本研究揭示了溶酶体蛋白Ragulator复合物（Ragulator complex）在NLRP3炎症小体激活中的关键作用。Ragulator复合物的核心组分Lamtor1的缺失，会阻断小鼠巨噬细胞与人单核细胞中NLRP3炎症小体的激活。髓系特异性Lamtor1缺陷小鼠的NLRP3相关炎症性疾病严重程度显著减轻，此类疾病包括脂多糖（LPS）诱导的脓毒症、明矾诱导的腹膜炎以及尿酸单钠（MSU，monosodium urate）诱导的关节炎。机制层面，在NLRP3炎症小体激活过程中，Lamtor1会与组蛋白去乙酰化酶6（HDAC6，histone deacetylase 6）发生相互作用，该相互作用可增强Ragulator复合物与NLRP3的结合。HDAC6的缺失会削弱Lamtor1与NLRP3之间的相互作用，进而导致NLRP3炎症小体激活不足。此外，DL-消旋-α-生育酚（DL-all-rac-α-tocopherol）可抑制Lamtor1与HDAC6的相互作用，从而减少NLRP3炎症小体的激活。DL-消旋-α-生育酚还能缓解急性痛风性关节炎与MSU诱导的腹膜炎。本研究结果阐明了溶酶体通过Ragulator复合物为NLRP3炎症小体的激活提供平台的作用机制。