Beijing Institute of Basic Medical Sciences, Beijing, China.
Anhui Medical University, Hefei, China.
Elife. 2021 Jun 10;10:e66501. doi: 10.7554/eLife.66501.
Nuclear factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering stress granule (SG) formation. However, the regulation of the NF90-SG pathway remains largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SG-mediated antiviral immunity. Vesicular stomatitis virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages, which in turn recruit the E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90 and initiate a proteasome-dependent degradation via K48-linked ubiquitination at Lys297. Targeted inactivation of Tim-3 enhances the NF90 downstream SG formation by selectively increasing the phosphorylation of protein kinase R and eukaryotic translation initiation factor 2α, the expression of SG markers G3BP1 and TIA-1, and protecting mice from VSV challenge. These findings provide insights into the crosstalk between Tim-3 and other receptors in antiviral innate immunity and its related clinical significance.
核因子 90（NF90）是一种新型的病毒传感器，通过触发应激颗粒（SG）形成来启动抗病毒先天免疫。然而，NF90-SG 途径的调节在很大程度上仍不清楚。我们发现，免疫检查点抑制剂 Tim-3 促进 NF90 的泛素化和降解，并抑制 NF90-SG 介导的抗病毒免疫。水疱性口炎病毒（VSV）感染诱导巨噬细胞中 Tim-3 的上调和激活，Tim-3 反过来招募 E3 泛素连接酶 TRIM47 到 NF90 的锌指结构域，并通过 K48 连接的泛素化在 Lys297 处启动蛋白酶体依赖性降解。Tim-3 的靶向失活通过选择性增加蛋白激酶 R 和真核翻译起始因子 2α 的磷酸化、SG 标志物 G3BP1 和 TIA-1 的表达，增强 NF90 下游 SG 的形成，从而保护小鼠免受 VSV 攻击。这些发现为 Tim-3 与抗病毒先天免疫中的其他受体之间的相互作用及其相关的临床意义提供了新的认识。
