The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding
The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding
复制标题
锌指蛋白 ZFYVE1 通过促进 TLR3 配体结合来调节 TLR3 介导的信号传导
DOI：
10.1038/s41423-019-0265-6
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发表时间：
2020-07-01
影响因子：
24.1
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
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作者：
Zhong, Xuan;Feng, Lu;Shu, Hong-Bing
Toll样受体3（TLR 3）对病毒dsRNA的识别导致下游抗病毒效应物的诱导和先天性抗病毒免疫应答。在这里，我们确定了锌指FYVE结构域的蛋白ZFYVE 1，鸟苷酸结合蛋白（GBP），作为TLR 3介导的信号传导的正调控。ZFYVE 1的过表达在用合成的TLR 3配体poly（I：C）刺激时促进下游抗病毒基因的转录。相反，ZFYVE 1缺陷具有相反的效果，Zfyve 1 −/−小鼠比野生型小鼠对poly（I：C）而不是LPS诱导的炎性死亡不敏感。ZFYVE 1与TLR 3相关，并且ZFYVE 1的FYVE结构域和TLR 3的胞外结构域被证明负责它们的相互作用。ZFYVE 1与poly（I：C）结合，并增加TLR 3与poly（I：C）的结合亲和力。这些发现表明ZFYVE 1通过促进TLR 3的配体结合在TLR 3介导的先天免疫和炎症反应中起重要作用。
Recognition of viral dsRNA by Toll-like receptor 3 (TLR3) leads to the induction of downstream antiviral effectors and the innate antiviral immune response. Here, we identified the zinc-finger FYVE domain-containing protein ZFYVE1, a guanylate-binding protein (GBP), as a positive regulator of TLR3-mediated signaling. Overexpression of ZFYVE1 promoted the transcription of downstream antiviral genes upon stimulation with the synthetic TLR3 ligand poly(I:C). Conversely, ZFYVE1 deficiency had the opposite effect.Zfyve1−/−mice were less susceptible than wild-type mice to inflammatory death induced by poly(I:C) but not LPS. ZFYVE1 was associated with TLR3, and the FYVE domain of ZFYVE1 and the ectodomain of TLR3 were shown to be responsible for their interaction. ZFYVE1 was bound to poly(I:C) and increased the binding affinity of TLR3 to poly(I:C). These findings suggest that ZFYVE1 plays an important role in the TLR3-mediated innate immune and inflammatory responses by promoting the ligand binding of TLR3.