After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models.

在识别其配体脂多糖后，Toll 样受体 4 (TLR4) 将接头蛋白招募到细胞膜上，从而启动下游信号传导并引发炎症。接头蛋白的募集是否仅依赖于蛋白质-蛋白质相互作用尚不清楚。在这里，我们报告鞘脂二氢鞘氨醇与接头蛋白 MyD88 和 TIRAP 发生物理相互作用，并促进巨噬细胞中 MyD88 的募集。丝氨酸棕榈酰转移酶长链碱基亚基 2 （编码催化鞘脂生物合成的关键酶）的骨髓细胞特异性缺陷，会减少 MyD88 的膜募集并抑制体外骨髓源性巨噬细胞和体内脓毒症模型中的炎症反应。在黑色素瘤小鼠模型中，丝氨酸棕榈酰转移酶长链碱基亚基 2缺陷会降低抗肿瘤骨髓细胞反应并增加肿瘤生长。因此，二氢鞘氨醇生物合成是 TLR4 信号转导启动所必需的，并可作为脓毒症和黑色素瘤小鼠模型中巨噬细胞模式识别的检查点。