Qin Jinzhong, Qian Youcun, Yao Jianhong, Grace Cui, Li Xiaoxia
Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
J Biol Chem. 2005 Jul 1;280(26):25233-41. doi: 10.1074/jbc.M501363200. Epub 2005 May 2.
The Toll-interleukin-1 receptor (TIR) domain-containing orphan receptor SIGIRR (single immunoglobulin interleukin-1 receptor-related protein) acts as a negative regulator of interleukin (IL)-1 and lipopolysaccharide (LPS) signaling. Endogenous SIGIRR transiently interacted with IL-1 receptor and the receptor-proximal signaling components (MyD88, IRAK, and tumor necrosis factor receptor-associated factor 6) upon IL-1 stimulation, indicating that SIGIRR interacts with the IL-1 receptor complex in a ligand-dependent manner. Similar interaction was also observed between SIGIRR and Toll-like receptor 4 receptor complex upon LPS stimulation. To identify the domains of SIGIRR required for its interaction with the Toll-like receptor 4 and IL-1 receptor complexes, several SIGIRR deletion mutants were generated, including DeltaN (lacking the extracellular immunoglobulin (Ig) domain with deletion of amino acids 1-119), DeltaC (lacking the C-terminal domain with deletion of amino acids 313-410), and DeltaTIR (lacking the TIR domain with deletion of amino acids 161-313). Whereas both the extracellular Ig domain and the intracellular TIR domains are important for SIGIRR to inhibit IL-1 signaling, only the TIR domain is necessary for SIGIRR to inhibit LPS signaling. The extracellular Ig domain exerts its inhibitory role in IL-1 signaling by interfering with the heterodimerization of IL-1 receptor and IL-1RAcP, whereas the intracellular TIR domain inhibits both IL-1 and LPS signaling by attenuating the recruitment of receptor-proximal signaling components to the receptor. These results indicate that SIGIRR inhibits IL-1 and LPS signaling pathways through differential mechanisms.
含Toll样白细胞介素-1受体（TIR）结构域的孤儿受体SIGIRR（单免疫球蛋白白细胞介素-1受体相关蛋白）作为白细胞介素（IL）-1和脂多糖（LPS）信号传导的负调节因子。在IL-1刺激下，内源性SIGIRR与IL-1受体及受体近端信号传导成分（髓样分化因子88、白细胞介素-1受体相关激酶和肿瘤坏死因子受体相关因子6）短暂相互作用，表明SIGIRR以配体依赖的方式与IL-1受体复合物相互作用。在LPS刺激下，SIGIRR与Toll样受体4受体复合物之间也观察到类似的相互作用。为了确定SIGIRR与Toll样受体4和IL-1受体复合物相互作用所需的结构域，构建了几个SIGIRR缺失突变体，包括DeltaN（缺失氨基酸1-119的细胞外免疫球蛋白（Ig）结构域）、DeltaC（缺失氨基酸313-410的C末端结构域）和DeltaTIR（缺失氨基酸161-313的TIR结构域）。虽然细胞外Ig结构域和细胞内TIR结构域对SIGIRR抑制IL-1信号传导都很重要，但只有TIR结构域是SIGIRR抑制LPS信号传导所必需的。细胞外Ig结构域通过干扰IL-1受体和IL-1受体辅助蛋白的异二聚化在IL-1信号传导中发挥其抑制作用，而细胞内TIR结构域通过减弱受体近端信号传导成分向受体的募集来抑制IL-1和LPS信号传导。这些结果表明，SIGIRR通过不同机制抑制IL-1和LPS信号通路。
