Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection

作者：Qingzhu Shi, Ge Li, Shuaijie Dou, Lili Tang, Chunmei Hou, Zhiding Wang, Yang Gao, Zhenfang Gao, Ying Hao, Rongliang Mo, Beifen Shen, Renxi Wang, Yuxiang Li, Gencheng Han · 发表于：Immunological Investigations · 年份：2022 · DOI：10.1080/08820139.2022.2113407 · 被引用次数：12 · 研究领域：interferon and immune responses、Inflammasome and immune disorders、Immune Response and Inflammation

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.