Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Cytosolic DNA triggers cyclic GMP-AMP synthase (cGAS) to produce cGAMP, initiating type I interferon expression.
• Mitochondrial DNA release during viral infections can activate cGAS, but regulatory mechanisms remain unclear.

Purpose of the Study:

• To investigate the regulatory mechanism of mitochondrial DNA-mediated cGAS activation.
• To identify proteins interacting with cGAS in macrophages during viral infection.

Main Methods:

• Proteomic analysis of cGAS interactome in RAW264.7 macrophages.
• Cellular and in vitro assays to assess C1QBP's effect on cGAS activity.
• Analysis of innate immune responses and HSV-1 infection in C1QBP-deficient and overexpressing cells.

Main Results:

• C1QBP was identified as a cGAS-interacting protein, predominantly localized in mitochondria.
• C1QBP translocates to the cytosol during DNA virus infection and inhibits cGAS enzymatic activity.
• C1QBP overexpression suppressed DNA-induced innate immunity and enhanced HSV-1 infection, while C1QBP deficiency had opposite effects.

Conclusions:

• C1QBP acts as a novel mitochondrial inhibitor of cGAS.
• C1QBP plays a crucial role in regulating innate immune responses to cytosolic DNA and viral infections.