PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation.

Virus infection stimulates proto-oncoprotein PIM1 kinase expression, but its importance and the biological functions of this process are poorly understood. Herein, PIM1 promotes IFNAR1 degradation to attenuate cellular innate immunity during human coronavirus HCoV-OC43 infection. During virus replication, the double-stranded viral RNA and some viral proteins upregulate PIM1 expression, which phosphorylates E3 ubiquitin ligase β-TrCP1 at Serine 82. The pS82-β-TrCP1 then forms a complex with S535/S539-phosphorylated interferon receptor IFNAR1 (pS535/539-IFNAR1), leading to IFNAR1 ubiquitination and degradation. Both pan-inhibitors (CX-6528, SGI-1776, AZD-1208) and a specific inhibitor of PIM1 kinase (PIM1 inhibitor 2) effectively block this process and potently inhibit viral replication. This studies demonstrate a novel strategy that viruses use to disrupt cellular innate immunity, suggesting a potential therapeutic target for further anti-virus drug development.