Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling
Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling
复制标题
DOI：
10.1093/glycob/cwx075
复制
发表时间：
2017-11-01
期刊：
影响因子：
4.3
通讯作者：
Taniguchi, Naoyuki
中科院分区：
文献类型：
--
作者：
Iijima, Junko;Kobayashi, Satoshi;Taniguchi, Naoyuki
核心岩藻糖基化是N-聚糖的翻译后修饰，修饰几种生长因子受体并影响其配体结合亲和力。通过消融α 1，6岩藻糖基转移酶Fut 8产生的核心岩藻糖缺陷小鼠表现出严重的肺气肿，部分原因是巨噬细胞功能受损，与老年Toll样受体4（Tlr 4）缺陷小鼠相似。因此，我们怀疑核心岩藻糖的缺乏会影响TLR 4依赖性信号通路。事实上，在脂多糖刺激下，Fut 8缺陷型小鼠胚胎成纤维细胞（MEFs）产生类似水平的白细胞介素-6，但与野生型MEFs相比，干扰素-β（IFN-β）的水平显着降低。TLR 4信号传导复合物的凝集素印迹分析揭示了在CD 14上特异性地发现核心岩藻糖基化。尽管在脂多糖刺激后Fut 8缺陷细胞中观察到类似水平的TLR 4/髓样分化因子2（MD 2）活化和二聚化，但TLR 4和CD 14的内化显著受损。鉴于内化的TLR 4/MD 2诱导IFN-β产生，Fut 8缺陷细胞中IFN-β产生受损归因于TLR 4/MD 2内化受损。这些数据首次表明糖基化对TLR 4信号传导具有重要调节作用。
Core fucosylation, a posttranslational modification of N-glycans, modifies several growth factor receptors and impacts on their ligand binding affinity. Core-fucose-deficient mice generated by ablating the alpha 1,6 fucosyltransferase enzyme, Fut8, exhibit severe pulmonary emphysema, partly due to impaired macrophage function, similar to aged Toll-like receptor 4 (Tlr4)-deficient mice. We therefore suspect that a lack of core fucose affects the TLR4-dependent signaling pathway. Indeed, upon lipopolysaccharide stimulation, Fut8-deficient mouse embryonic fibroblasts (MEFs) produced similar levels of interleukin-6 but markedly reduced levels of interferon-beta (IFN-beta) compared with wild-type MEFs. Lectin blot analysis of the TLR4 signaling complex revealed that core fucosylation was specifically found on CD14. Even though similar levels of TLR4/myeloid differentiation factor 2 (MD2) activation and dimerization were observed in Fut8-deficient cells after lipopolysaccharide stimulation, internalization of TLR4 and CD14 was significantly impaired. Given that internalized TLR4/MD2 induces IFN-beta production, impaired IFN-beta production in Fut8-deficient cells is ascribed to impaired TLR4/MD2 internalization. These data show for the first time that glycosylation critically regulates TLR4 signaling.