E3 ubiquitin ligase MID1 ubiquitinates and degrades type‐I interferon receptor 2. Issue 3 (23rd July 2022)

• Record Type: Journal Article
• Authors: Chen, Xiangjie; Zhao, Qian; Xu, Ying; Wu, Qiuyu; Zhang, Renxia; Du, Qian; Miao, Ying; Zuo, Yibo; Zhang, Hong‐Guang; Huang, Fan; Ren, Tengfei; He, Jiuyi; Qiao, Caixia; Li, Yue; Li, Shifeng; Xu, Yang; Wu, Depei; Yu, Zhengyuan; Lv, Haitao; Wang, Jun; Zheng, Hui; Yuan, Yukang
• Is Part Of: Immunology. Volume 167:Issue 3(2022)
• Page Start: 398
• Page End: 412
• Publication Date: 2022-07-23
• Subjects: antiviral response -- IFNAR2 -- innate immunity -- interferon -- MID1 -- ubiquitination; Immunology -- Periodicals
• DOI: 10.1111/imm.13544
• Languages: English
• ISSNs: 0019-2805

Abstract

Abstract: 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. Abstract : Prolonged type I interferon (IFN‐I) stimulation upregulates the expression of the E3 ubiquitin ligase MID1. MID1 then ubiquitinates and degrades IFNAR2, a key receptor for the IFN‐I signaling pathway, in a lysosome‐dependent manner. This leads to inhibition of the IFN signaling pathway.