The leaked mitochondrial C1QBP inhibits activation of the DNA sensor cGAS

Abstract

Abstract Cytosolic DNA released from microbial pathogens triggers the activation of DNA sensor cyclic GMP-AMP synthase (cGAS) which catalyzes the synthesis of the cyclic GMP-AMP (cGAMP), a second messenger that triggers a signaling cascade leading to type I interferon (IFN) production. The cGAS cannot discriminate the origin and sequence of dsDNA; thus, it is also activated by self-DNA leaked from the nucleus or the mitochondria. Recent studies have shown that DNA virus infection triggers mitochondrial stress, leading to the release of mtDNA to the cytosol and activation of cGAS; however, the regulatory mechanism of the mtDNA-mediated cGAS activation is not well elucidated. To seek potential regulators for cGAS, we used proteomics to map the protein interactome of cGAS in macrophages and found C1QBP as a novel binding partner of cGAS. C1QBP is predominantly localized in the mitochondria matrix and leaked to the cytosol upon DNA virus infection. C1QBP binds to the NTase domain of cGAS and inhibits the cGAS activity in cells and in vitro. Overexpression of the cytosolic form of C1QBP inhibited the cytosolic DNA-induced immune response and facilitated HSV-1 infection. By contrast, deficiency of C1QBP leads to elevated innate immune responses and impaired HSV-1 infection. Taken together, our study suggests that C1QBP is a cGAS inhibitor hidden in the mitochondria.