E3 ubiquitin ligase MID1 ubiquitinates and degrades type‐I interferon receptor 2

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. 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.