State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China.
School of Biological and Chemical Engineering, College of Zhixing, Hubei University, Wuhan, 430011, China.
Cell Mol Immunol. 2021 Jul;18(7):1708-1717. doi: 10.1038/s41423-020-0411-1. Epub 2020 Mar 31.
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.
toll 样受体 (TLR) 信号通路需要严格控制，以避免过度炎症和宿主的不必要损伤。髓样分化初级反应基因 88 (MyD88) 是 TLR 信号的关键衔接蛋白。在这里，我们鉴定出斑点型 POZ 蛋白 (SPOP) 是 MyD88 相关蛋白。TLR4 激活后，SPOP 被招募到 MyD88。TLR4 激活还导致 SPOP 从核内易位到细胞质。SPOP 耗竭促进了 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 的激活和炎症细胞因子的产生，而 SPOP 耗竭则产生相反的效果。此外，SPOP 的敲低增加了 TLR2、TLR7 和 TLR9 激活时 MyD88 的聚集和炎症细胞因子的产生。我们的研究结果揭示了 MyD88 被调控的机制，并强调了 SPOP 在限制炎症反应中的作用。
