RNF213 Is an Interferon-Stimulated Gene That Targets Influenza A Virus NP and Activates MDA5 to Restrict Infection

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Influenza A virus (IAV) infection triggers a type I interferon (IFN) response, activating interferon-stimulated genes (ISGs) with antiviral functions.
• The precise mechanisms and specific ISGs involved in controlling IAV remain incompletely understood.

Purpose of the Study:

• To systematically identify antiviral ISGs against IAV.
• To elucidate the antiviral mechanisms of ring finger protein 213 (RNF213) in host cells and its role in IAV infection.

Main Methods:

• Systematic identification of antiviral ISGs in A549 cells after type I and type II IFN treatment.
• In vitro assays to assess RNF213's inhibition of IAV replication.
• Analysis of RNF213 knockout (KO) mice susceptibility to IAV.
• Investigation of RNF213's interaction with MDA5 and its ubiquitination status.
• Assessment of RNF213's role in viral nucleoprotein (NP) degradation.

Main Results:

• RNF213 was identified as a potent inhibitor of IAV replication in vitro.
• RNF213 knockout mice showed increased susceptibility and disease severity upon IAV infection.
• RNF213 amplifies IFN production by enhancing MDA5 signaling through K63-linked polyubiquitination.
• RNF213 mediates K48-linked polyubiquitination and proteasomal degradation of viral NP.

Conclusions:

• RNF213 is a critical antiviral ISG that bridges innate immune activation and direct viral restriction against IAV.
• RNF213 exhibits a dual antiviral mechanism involving IFN pathway enhancement and viral protein degradation.
• RNF213 represents a promising therapeutic target for influenza treatment.