Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China.
School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
Immunology. 2022 Nov;167(3):398-412. doi: 10.1111/imm.13544. Epub 2022 Jul 23.
Type I interferon (IFN-I) is a common biological molecule used for the treatment of viral diseases. However, the clinical antiviral efficacy of IFN-I needs to be greatly improved. In this study, IFN-I receptor 2 (IFNAR2) was revealed to undergo degradation at the protein level in cells treated with IFN-I for long periods of time. Further studies found a physical interaction between the E3 ubiquitin ligase midline-1 (MID1) and IFNAR2. As a consequence, MID1 induced both K48- and K63-linked polyubiquitination of IFNAR2, which promoted IFNAR2 protein degradation in a lysosome-dependent manner. Conversely, knockdown of MID1 largely restricted IFN-I-induced degradation of IFNAR2. Importantly, MID1 regulated the strength of IFN-I signalling and IFN-I-induced antiviral activity. These findings reveal a regulatory mechanism of IFNAR2 ubiquitination and protein stability in IFN-I signalling, which could provide a potential target for improving the antiviral efficacy of IFN-I.
I 型干扰素（IFN-I）是一种常用于治疗病毒疾病的常见生物分子。然而，IFN-I 的临床抗病毒疗效需要大大提高。在这项研究中，发现在用 IFN-I 处理细胞很长一段时间后，IFN-I 受体 2（IFNAR2）在蛋白质水平上发生降解。进一步的研究发现 E3 泛素连接酶中线 1（MID1）与 IFNAR2 之间存在物理相互作用。结果，MID1 诱导 IFNAR2 的 K48-和 K63 连接多泛素化，从而以溶酶体依赖性方式促进 IFNAR2 蛋白降解。相反，MID1 的敲低在很大程度上限制了 IFN-I 诱导的 IFNAR2 降解。重要的是，MID1 调节 IFN-I 信号转导和 IFN-I 诱导的抗病毒活性的强度。这些发现揭示了 IFN-I 信号转导中 IFNAR2 泛素化和蛋白质稳定性的调节机制，可为提高 IFN-I 的抗病毒疗效提供潜在目标。
