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The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediates innate immune responses against invading pathogens, or against self-dsDNA, which causes autoimmune disorders. Upon nonspecific binding of cytosolic B-form DNA, cGAS synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent signaling to produce type I IFNs. The cGAS comprises less-conserved N-terminal residues and highly conserved nucleotidyltransferase/Mab21 domains. The function and structure of the well-conserved domains have been extensively studied, whereas the physiological function of the N-terminal domain of cGAS is largely uncharacterized. In this study we used a single-molecule technique combined with traditional biochemical and cellular assays to demonstrate that binding of nonspecific dsDNA by the N-terminal domain of cGAS promotes its activation. We have observed that the N terminus of human cGAS ( h cGAS-N160) undergoes secondary structural change upon dsDNA binding in solution. Furthermore, we showed that the h cGAS-N160 helps full length h cGAS to expand the binding range on λDNA and facilitates its binding efficiency to dsDNA compared with h cGAS without the 160 N-terminal residues ( h cGAS-d160). More importantly, h cGAS-N160 endows full length h cGAS relatively higher enzyme activity and stronger activation of STING/IRF3-mediated cytosolic DNA signaling. These findings strongly indicate that the N-terminal domain of cGAS plays an important role in enhancing its function.

Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation