USP12 promotes antiviral responses by deubiquitinating and stabilizing IFI16

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Deubiquitinating enzymes (DUBs) are critical regulators of innate antiviral immunity.
• Interferon-gamma inducible protein 16 (IFI16) is a key DNA sensor involved in antiviral signaling via the STING/TBK-1/IRF3 pathway.
• The role of specific DUBs, like Ubiquitin-specific protease 12 (USP12), in modulating nucleic acid sensor-mediated antiviral responses remains largely unexplored.

Purpose of the Study:

• To investigate the function of USP12 in the context of DNA sensor signaling and antiviral immunity.
• To elucidate the mechanism by which USP12 influences the IFI16-mediated antiviral response against viral infections, specifically HSV-1.

Main Methods:

• Utilized gene knockout and knockdown techniques to assess USP12 function.
• Measured the expression of antiviral cytokines (IFN-β, CCL-5, IL-6) and interferon-stimulated genes (ISGs) following HSV-1 infection.
• Assessed viral replication and host susceptibility to HSV-1 in USP12-deficient cells.
• Investigated the effect of USP12 on IFI16 protein stability and degradation pathways.

Main Results:

• Knockout or knockdown of USP12 significantly impaired HSV-1-induced expression of IFN-β, CCL-5, IL-6, and ISGs.
• USP12 deficiency led to increased HSV-1 replication and heightened host susceptibility to HSV-1 infection.
• Mechanistically, USP12 was found to inhibit the proteasome-dependent degradation of IFI16 via its deubiquitinase activity.
• USP12 maintains IFI16 stability, thereby promoting IFI16-STING-IRF3 and p65-mediated antiviral signaling.

Conclusions:

• USP12 plays an essential role in DNA sensing signaling pathways and innate antiviral responses.
• USP12 stabilizes IFI16, a key DNA sensor, thereby enhancing the antiviral immune response against viral pathogens like HSV-1.
• These findings highlight the importance of deubiquitination in regulating innate antiviral immunity and identify USP12 as a potential therapeutic target.