Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.
IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
Nat Commun. 2017 Jan 18;8:14133. doi: 10.1038/ncomms14133.
Danger signals activate Toll-like receptors (TLRs), thereby initiating inflammatory responses. Canonical TLR signalling, via Toll/Interleukin-1 receptor domain (TIR)-containing adaptors and proinflammatory transcription factors such as NF-κB, occurs in many cell types; however, additional mechanisms are required for specificity of inflammatory responses in innate immune cells. Here we show that SCIMP, an immune-restricted, transmembrane adaptor protein (TRAP), promotes selective proinflammatory cytokine responses by direct modulation of TLR4. SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. Point mutations in SCIMP abrogating TLR4 binding also prevent SCIMP-mediated cytokine production. SCIMP is, therefore, an immune-specific TLR adaptor that shapes host defence and inflammation.
危险信号激活 Toll 样受体 (TLR)，从而引发炎症反应。经典的 TLR 信号通路通过 Toll/白细胞介素-1 受体结构域 (TIR) 包含的衔接子和 NF-κB 等促炎转录因子在许多细胞类型中发生；然而，在先天免疫细胞中，炎症反应的特异性还需要其他机制。在这里，我们表明，SCIMP，一种免疫受限的跨膜衔接蛋白 (TRAP)，通过直接调节 TLR4 促进选择性的促炎细胞因子反应。SCIMP 是一种非 TIR 包含的衔接子，可直接与 TLR4-TIR 结构域结合，以响应脂多糖。在巨噬细胞中，SCIMP 与 Lyn 酪氨酸激酶持续相关，是 TLR4 酪氨酸磷酸化所必需的，并且有助于 TLR 诱导的促炎细胞因子 IL-6 和 IL-12p40 的产生。破坏 TLR4 结合的 SCIMP 点突变也阻止了 SCIMP 介导的细胞因子产生。因此，SCIMP 是一种免疫特异性的 TLR 衔接子，可塑造宿主防御和炎症。
