Researchers reveal safeguarding of key DNA sensor in innate immune system

UNC-Chapel Hill researchers have, for the first time, determined the high-resolution structure of a key DNA-sensing protein in the innate immune system called cGAS while it is bound to the nucleosome—the all-important unit of DNA packaging inside a cell's nucleus.

This research, published in Science , reveals in detail how the nucleosomes inside our cells block cGAS from unintentionally triggering the body's innate immune response to our own DNA.

"A deeper understanding of functions and regulations of this important DNA sensor will have profound impacts on both basic research and translational development of cGAS-targeted therapeutics crucial to the betterment of human health."

McGinty, co-senior author, said, "This work was enabled by recent advances in cryo-electron microscopy technology that allows scientists, like those on our team, to observe the protein machines inside our cells with unprecedented clarity.

Upon DNA detection, cGAS synthesizes cyclic GMP-AMP (cGAMP), the second messenger molecule that activates the cGAS-STING signaling pathway to fight infections, inflammatory diseases, and cancers.

Using the UNC School of Medicine state-of-the-art Cryo-Electron Microscopy Core Facility, which was established in 2019, the Zhang and McGinty labs determined a 3.3Å-resolution cryo-EM structure of cGAS in complex with the nucleosome.

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