Toll-like receptor (TLR) signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host. Myeloid differentiation primary response gene 88 (MyD88) is a critical adaptor of TLR signaling. Here, we identified the speckle-type POZ protein (SPOP) as a MyD88-associated protein. SPOP was recruited to MyD88 following TLR4 activation. TLR4 activation also caused the translocation of SPOP from the nucleus to the cytoplasm. SPOP depletion promoted the aggregation of MyD88 and recruitment of the downstream signaling kinases IRAK4, IRAK1 and IRAK2. Consistently, overexpression of SPOP inhibited the TLR4-mediated activation of NF-κB and production of inflammatory cytokines, whereas SPOP depletion had the opposite effects. Furthermore, knockdown of SPOP increased MyD88 aggregation and inflammatory cytokine production upon TLR2, TLR7 and TLR9 activation. Our findings reveal a mechanism by which MyD88 is regulated and highlight a role for SPOP in limiting inflammatory responses.

需要严格控制 Toll 样受体 (TLR) 信号通路，以避免过度炎症和对宿主造成不必要的损害。骨髓分化初级反应基因 88 (MyD88) 是 TLR 信号转导的关键适配器。在这里，我们将斑点型 POZ 蛋白 (SPOP) 鉴定为 MyD88 相关蛋白。在 TLR4 激活后，SPOP 被招募到 MyD88。TLR4 激活还导致 SPOP 从细胞核转移到细胞质。SPOP 消耗促进了 MyD88 的聚集和下游信号激酶 IRAK4、IRAK1 和 IRAK2 的募集。一致地，SPOP 的过表达抑制了 TLR4 介导的 NF-κB 活化和炎性细胞因子的产生，而 SPOP 消耗具有相反的效果。此外，在 TLR2、TLR7 和 TLR9 激活时，SPOP 的敲低增加了 MyD88 的聚集和炎性细胞因子的产生。我们的研究结果揭示了 MyD88 的调节机制，并强调了 SPOP 在限制炎症反应中的作用。