The human immune system deploys an array of sensors to detect invading pathogens like viruses. One of these sensors, the human enzyme cGAS, detects invading DNA and initiates an antiviral response by producing a unique signaling molecule known as a cyclic dinucleotide. Cyclic dinucleotide signals are also found in bacteria, but previously no direct connection existed between the signaling pathways in bacteria and human immunity. Jennifer Doudna, James Berger, and colleagues now show that a bacterial signaling protein critical for pathogenesis in Vibrio cholerae is actually a homolog of human cGAS. These results reveal a surprising evolutionary connection between bacterial signaling and human innate immunity.
Additionally, comparison of structures of the two enzymes reveals a mechanism to explain chemical differences between bacterial and human cyclic dinucleotide signals, and explains how human cGAS produces a unique molecule to warn of invading bacterial and viral pathogens.
Work performed on ALS Beamline 8.3.1.
Citation: Philip J. Kranzusch, Amy S.Y. Lee,Stephen C. Wilson, Mikhail S. Solovykh, Russell E. Vance, James M. Berger, and Jennifer A. Doudna, “Structure-Guided Reprogramming of Human cGAS Dinucleotide Linkage Specificity,” Cell 158, 1011 (2014), doi:http://dx.doi.org/10.1016/j.cell.2014.07.028.