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

Area of Science:

• Virology
• Immunology
• Molecular Biology
• Oncology

Background:

• Virus infections can stimulate proto-oncoprotein PIM1 kinase expression, but its role in immunity is unclear.
• Understanding PIM1's function during viral infections is crucial for developing antiviral strategies.

Purpose of the Study:

• To investigate the role of PIM1 kinase in cellular innate immunity during human coronavirus HCoV-OC43 infection.
• To elucidate the molecular mechanism by which PIM1 affects the interferon receptor IFNAR1.
• To evaluate the therapeutic potential of PIM1 inhibitors against HCoV-OC43.

Main Methods:

• Investigated PIM1 expression during HCoV-OC43 infection.
• Examined the phosphorylation of E3 ubiquitin ligase β-TrCP1 by PIM1.
• Assessed the interaction between phosphorylated β-TrCP1 and phosphorylated IFNAR1.
• Utilized pan-PIM inhibitors (CX-6528, SGI-1776, AZD-1208) and a specific PIM1 inhibitor (PIM1 inhibitor 2) to block the pathway.
• Measured the effect of inhibitors on viral replication.

Main Results:

• PIM1 promotes the degradation of interferon receptor IFNAR1, thereby attenuating innate immunity during HCoV-OC43 infection.
• Viral RNA and proteins upregulate PIM1, which phosphorylates β-TrCP1.
• Phosphorylated β-TrCP1 complexes with phosphorylated IFNAR1, leading to IFNAR1 ubiquitination and degradation.
• PIM1 inhibition effectively blocks IFNAR1 degradation and significantly inhibits viral replication.

Conclusions:

• Viruses employ PIM1 to degrade IFNAR1, a novel mechanism to evade innate immunity.
• Targeting PIM1 kinase represents a promising therapeutic strategy for antiviral drug development against HCoV-OC43 and potentially other viruses.
• This study reveals a critical interplay between viral infection, PIM1 kinase, and the host innate immune system.