Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection
Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection
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DOI：
10.1080/08820139.2022.2113407
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发表时间：
2022-08
影响因子：
2.8
通讯作者：
Qingzhu Shi;Ge Li;Shuaijie Dou;Lili Tang;C. Hou;Zhiding Wang;Yang Gao;Zhenfang Gao;Ying Hao;Rongliang Mo;B. Shen;R. Wang;Yuxiang Li;G. Han
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文献类型：
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作者：
Qingzhu Shi;Ge Li;Shuaijie Dou;Lili Tang;C. Hou;Zhiding Wang;Yang Gao;Zhenfang Gao;Ying Hao;Rongliang Mo;B. Shen;R. Wang;Yuxiang Li;G. Han
摘要 视黄酸诱导基因 I (RIG-I) 作为一种重要的 RNA 病毒传感器，在许多生物和病理过程中的调节机制仍有待确定。在这里，我们证明 T 细胞免疫球蛋白和粘蛋白蛋白 3 (Tim-3)（一种免疫检查点抑制剂）通过抑制 RIG-I-I 型干扰素途径介导感染耐受性。 Tim-3 的过度表达或阻断会影响 H1N1 感染后小鼠的 I 型干扰素表达、病毒复制和组织损伤。 Tim-3 信号传导通过巨噬细胞中的 STAT1 减少 RIG-I 转录，并通过 E3 连接酶 RNF-122 增强 K-48 连接的泛素化，促进 RIG-I 的蛋白酶体依赖性降解。沉默 RIG-I 可逆转 Tim-3 阻断介导的巨噬细胞中 I 型干扰素的上调。因此，我们发现了 Tim-3 介导 H1N1 免疫逃避的新机制，这可能对病毒性疾病的治疗具有临床意义。
ABSTRACT The mechanisms by which retinoic acid-inducible gene I (RIG-I), a critical RNA virus sensor, is regulated in many biological and pathological processes remain to be determined. Here, we demonstrate that T cell immunoglobulin and mucin protein-3 (Tim-3), an immune checkpoint inhibitor, mediates infection tolerance by suppressing RIG-I-type I interferon pathway. Overexpression or blockade of Tim-3 affects type I interferon expression, virus replication, and tissue damage in mice following H1N1 infection. Tim-3 signaling decreases RIG-I transcription via STAT1 in macrophages and promotes the proteasomal dependent degradation of RIG-I by enhancing K-48-linked ubiquitination via the E3 ligase RNF-122. Silencing RIG-I reversed Tim-3 blockage-mediated upregulation of type I interferon in macrophages. We thus identified a new mechanism through which Tim-3 mediates the immune evasion of H1N1, which may have clinical implications for the treatment of viral diseases.