ZNF593 regulates the cGAS-mediated innate immune response by attenuating cGAS-DNA binding

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Cyclic GMP-AMP synthase (cGAS) detects double-stranded DNA (dsDNA) to initiate innate immune responses via type I interferon (IFN-I) production.
• Dysregulated IFN-I signaling is implicated in autoimmune diseases such as systemic lupus erythematosus (SLE).

Purpose of the Study:

• To identify novel regulators of cGAS-mediated antiviral immunity.
• To investigate the role of ZNF593 in innate immune responses and autoimmune pathology.

Main Methods:

• Viral infection models in cell culture and mice.
• Co-immunoprecipitation assays to assess protein interactions.
• Analysis of interferon production and immune cell activation.
• Assessment of disease severity and survival rates in mouse models.

Main Results:

• ZNF593 translocates to the cytoplasm upon viral infection and directly binds to cGAS, inhibiting its activation by suppressing cGAS-dsDNA interaction.
• ZNF593 deficiency enhances IRF3 nuclear translocation and promotes DNA virus-triggered IFN-I production, improving mouse survival against HSV-1 infection.
• ZNF593 replenishment reduces IFN production in SLE patient cells and a murine SLE model, indicating a protective role in autoimmune pathology.

Conclusions:

• ZNF593 acts as a negative regulator of antiviral type I interferon production by targeting cGAS.
• ZNF593 plays a protective role in SLE pathogenesis, suggesting its therapeutic potential for autoimmune diseases.