TY - JOUR T1 - cGAS is predominantly a nuclear protein JF - bioRxiv DO - 10.1101/486118 SP - 486118 AU - Hannah E. Volkman AU - Stephanie Cambier AU - Elizabeth E. Gray AU - Daniel B. Stetson Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/12/04/486118.abstract N2 - cGAS is an intracellular innate immune sensor that detects double-stranded DNA. The presence of billions of base pairs of genomic DNA in all nucleated cells raises the question of how cGAS is not constitutively activated. A widely accepted explanation for this is the sequestration of cGAS in the cytosol, which is thought to prevent cGAS from accessing nuclear DNA. Here, we demonstrate that cGAS is predominantly a nuclear protein, regardless of cell cycle phase or cGAS activation status. We show that nuclear cGAS is tethered tightly by a salt-resistant interaction. This tight tethering is independent of the domains required for cGAS activation, and it requires intact nuclear chromatin. We propose that tethering prevents activation of cGAS by genomic DNA, and that it might enable cGAS to distinguish between self DNA and foreign DNA within the nucleus. ER -