Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
J Mol Cell Biol. 2020 May 18;12(4):251-262. doi: 10.1093/jmcb/mjaa004.
Toll-like receptor 3 (TLR3)-mediated signaling is important for host defense against RNA virus. Upon viral RNA stimulation, toll and interleukin-1 receptor domain-containing adaptor inducing IFN-β (TRIF) is recruited to TLR3 and then undergoes oligomerization, which is required for the recruitment of downstream molecules to transmit signals. Here, we identified zinc finger CCHC-type containing 3 (ZCCHC3) as a positive regulator of TLR3-mediated signaling. Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C). ZCCHC3-deficiency markedly inhibited TLR3- but not TLR4-mediated induction of type I interferons (IFNs) and proinflammatory cytokines. Zcchc3-/- mice were more resistant to poly(I:C)- but not lipopolysaccharide-induced inflammatory death. Mechanistically, ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(I:C) stimulation. Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.
Toll 样受体 3（TLR3）介导的信号转导对于宿主防御 RNA 病毒至关重要。在病毒 RNA 刺激下，Toll 和白细胞介素-1 受体结构域包含衔接蛋白诱导 IFN-β（TRIF）被招募到 TLR3 上，然后发生寡聚化，这是招募下游分子传递信号所必需的。在这里，我们鉴定出锌指 CCHC 型包含 3（ZCCHC3）作为 TLR3 介导的信号转导的正调节剂。ZCCHC3 的过表达促进了合成 TLR3 配体 poly(I:C) 刺激的下游抗病毒基因的转录。ZCCHC3 缺陷显著抑制了 TLR3 但不抑制 TLR4 介导的 I 型干扰素（IFN）和促炎细胞因子的诱导。Zcchc3-/- 小鼠对 poly(I:C)诱导的炎症性死亡更具抵抗力，但对脂多糖诱导的炎症性死亡没有抵抗力。在机制上，ZCCHC3 在 poly(I:C)刺激后促进 TRIF 向 TLR3 的募集。我们的发现表明，ZCCHC3 通过在配体刺激后促进 TRIF 向 TLR3 的募集，在 TLR3 介导的先天免疫反应中发挥重要作用。
