Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-κB activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-κB signaling pathway during macrophage activation.

包括 Toll 样受体 (TLR) 在内的模式识别受体可识别入侵的病原体并触发哺乳动物的免疫反应。在这里，我们展示了哺乳动物 ste20 样激酶 1/丝氨酸/苏氨酸激酶 4 (MST1/STK4) 作为脂多糖 (LPS) 诱导的与炎症相关的 TLR4-NF-κB 信号通路激活的负调节因子。 MST1/STK4 的骨髓特异性基因消融增加了小鼠对 LPS 诱导的感染性休克的易感性。 MST1/STK4 的消除还增强了骨髓源性巨噬细胞 (BMDM) 中 LPS 触发的 NF-κB 激活，导致这些细胞产生促炎细胞因子的增加。此外，MST1/STK4 抑制 TRAF6 自泛素化以及 LPS 诱导的 TRAF6 介导的下游信号传导。此外，我们发现TRAF6通过催化其泛素化来介导LPS诱导的MST1/STK4激活，导致MST1/STK4对LPS诱导的途径进行负反馈调节，导致巨噬细胞中细胞因子的产生。总之，我们的研究结果表明，MST1/STK4 在巨噬细胞激活过程中充当 LPS 诱导的 NF-κB 信号通路的负调节剂。