GPR108, an NF-κB activator suppressed by TIRAP, negatively regulates TLR-triggered immune responses

Higher vertebrates have evolved innate and adaptive immune systems to defend against foreign substances and pathogens. Sophisticated regulatory circuits are needed to avoid inappropriate immune responses and inflammation. GPR108 is a seven-transmembrane family protein that activates NF-κB strongly when overexpressed. Surprisingly, its action in a physiological context is that of an antagonist of Toll-like receptor (TLR)-mediated signaling. Cells from Gpr108-null mice exhibit enhanced cytokine secretion and NF-κB and IRF3 signaling, whereas Gpr108-null macrophages reconstituted with GPR108 exhibit blunted signaling. Co-expression of TLRs and GPR108 reduces NF-κB and IFNβ promoter activation compared to expression of either TLRs or GPR108 alone. Upon TLR stimulation GPR108 abundance increases and the protein engages TLRs and their partners to reduce MyD88 expression and interfere with its binding to TLR4 through blocking MyD88 ubiquitination. In turn GPR108 is antagonized by TIRAP, an adaptor protein for TLR and MyD88. The interrelationships between GPR108 and innate immune signaling components are multifactorial and point to a membrane-associated signaling structure of significant complexity.

高等脊椎动物演化出固有免疫与适应性免疫系统，用以抵御外来物质与病原体。机体需要精密的调控环路以避免异常免疫应答与炎症反应。GPR108是一种七次跨膜家族蛋白，过表达时可强力激活核因子κB（NF-κB）。令人意外的是，其在生理环境中的功能却是Toll样受体（Toll-like receptor, TLR）介导信号通路的拮抗剂。Gpr108敲除小鼠的细胞表现出增强的细胞因子分泌，以及NF-κB与干扰素调节因子3（IRF3）的信号通路激活；而通过GPR108重建的Gpr108敲除巨噬细胞，其信号转导则被显著削弱。与单独表达TLRs或GPR108相比，共表达TLRs与GPR108可降低NF-κB及干扰素β（IFNβ）启动子的激活水平。当TLR受到刺激时，GPR108的蛋白丰度升高，该蛋白可结合TLRs及其伴侣分子，下调髓系分化因子88（MyD88）的表达，并通过阻断MyD88的泛素化，干扰其与TLR4的结合。反过来，GPR108可被TIRAP拮抗——TIRAP是一种TLR与MyD88的接头蛋白。GPR108与固有免疫信号通路组分之间的相互关系具有多因素复杂性，提示存在一种结构极为复杂的膜相关信号复合体。