Interplay of cGAS with chromatin

The enzyme cGAS is an evolutionarily highly conserved major innate immune sensor of double-stranded DNA. cGAS is situated both inside the cell cytoplasm, where it can be readily activated, and inside the nucleus, where it is not active under normal conditions. Inside the nucleus, cGAS is tightly tethered to nucleosomes through complementary interfaces, which prevent its activation on genomic self-DNA. Non-nucleosome regulation is critical to control cGAS activity in contexts of loss of nuclear compartmentalization. Aberrant regulation of cGAS on chromatin is associated with inflammatory effector responses, senescence, and cell death. Recognition of DNA is an evolutionarily highly conserved mechanism of immunity. In mammals, the cGAS-STING pathway plays a central role in coupling DNA sensing to the execution of innate immune mechanisms, both in contexts of infection as well as in noninfectious settings of cellular stress and injury. The indiscriminate ability of double-stranded DNA (dsDNA) to activate cGAS challenges our understanding on how engagement of this pathway is prevented on genomic self-DNA under homeostatic conditions. Here, we review recent discoveries on the regulation of cGAS on chromatin and we discuss implications for cGAS-dependent inflammatory phenotypes. We close by highlighting emerging developments on the role of nuclear cGAS and related open questions for future research. Recognition of DNA is an evolutionarily highly conserved mechanism of immunity. In mammals, the cGAS-STING pathway plays a central role in coupling DNA sensing to the execution of innate immune mechanisms, both in contexts of infection as well as in noninfectious settings of cellular stress and injury. The indiscriminate ability of double-stranded DNA (dsDNA) to activate cGAS challenges our understanding on how engagement of this pathway is prevented on genomic self-DNA under homeostatic conditions. Here, we review recent discoveries on the regulation of cGAS on chromatin and we discuss implications for cGAS-dependent inflammatory phenotypes. We close by highlighting emerging developments on the role of nuclear cGAS and related open questions for future research. a major anchoring point shared amongst many nucleosome-binding proteins and formed by acidic residues of histone H2A and H2B, located at the surface of the nucleosome. chromatin bridges result from errors during mitosis and consist of strands of chromatin that connect segregating chromosomes during anaphase or daughter nuclei after completion of cytokinesis. CCFs locate to the cell cytosol, contain chromatin fragments encapsulated by a membrane, and were first described to be present in senescent cells. diseases that are caused by mutations of genes that encode components of the nuclear lamina. a physical process whereby components in a solution separate into two coexisting phases: one dense phase and one dilute phase. small cellular organelle, separated from the main nucleus, that contains genomic DNA and is surrounded by a nuclear envelope. web-like chromatin structures that are released by neutrophils in a programmed cell death process, called NETosis. the NCP is comprised of ~147 base pairs of dsDNA wrapped around a histone octamer, consisting of two copies of each of the core histones H2A, H2B, H3, and H4. (also retrotransposable elements), discrete pieces of DNA that can move within the genome and do so via the generation of an RNA intermediate. a transmembrane protein that functions as an intracellular receptor for endogenous and exogenous cyclic dinucleotides. the positions of major grooves of nucleosomal DNA that face the histone octamer. The central location of SHL0 is at the dyad and the numbering extends to SHL7.