TY - JOUR TI - The allosteric activation of cGAS underpins its dynamic signaling landscape AU - Hooy, Richard M AU - Sohn, Jungsan A2 - Krishnan, Yamuna A2 - Cole, Philip A VL - 7 PY - 2018 DA - 2018/10/08 SP - e39984 C1 - eLife 2018;7:e39984 DO - 10.7554/eLife.39984 UR - https://doi.org/10.7554/eLife.39984 AB - Cyclic G/AMP synthase (cGAS) initiates type-1 interferon responses against cytosolic double-stranded (ds)DNA, which range from antiviral gene expression to apoptosis. The mechanism by which cGAS shapes this diverse signaling landscape remains poorly defined. We find that substrate-binding and dsDNA length-dependent binding are coupled to the intrinsic dimerization equilibrium of cGAS, with its N-terminal domain potentiating dimerization. Notably, increasing the dimeric fraction by raising cGAS and substrate concentrations diminishes duplex length-dependent activation, but does not negate the requirement for dsDNA. These results demonstrate that reaction context dictates the duplex length dependence, reconciling competing claims on the role of dsDNA length in cGAS activation. Overall, our study reveals how ligand-mediated allostery positions cGAS in standby, ready to tune its signaling pathway in a switch-like fashion. KW - innate immunity KW - allostery KW - cGAS KW - cytoplasmic DNA KW - enzymology KW - mechanisms JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -