Editors' ChoiceImmunology

Activating cGAS at the right time and place

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Science Signaling  26 Mar 2019:
Vol. 12, Issue 574, eaax4336
DOI: 10.1126/scisignal.aax4336

Plasma membrane localization and acetylation ensure the appropriate activation of the DNA sensor cGAS.

DNA in the cytosol of cells, such as that which occurs during genotoxic stress or viral infection, induces the activation of cGAS, which generates the second messenger 2′3′-cyclic GMP-AMP (cGAMP). cGAMP triggers interferon (IFN) production and the expression of IFN-stimulated genes (ISGs). Two papers define mechanisms that regulate cGAS activation and prevent the recognition of self-DNA and the development of autoimmune diseases. Barnett et al. revealed that cGAS localization limits the recognition of self-DNA while maximizing responses to viral infection. In human THP1 cells and murine bone marrow–derived macrophages (BMDMs), cGAS was not localized to the cytosol, as had been previously assumed. Instead, cGAS was associated with the plasma membrane, a localization that required the binding of the phospholipid PI(4,5)P2 to the N terminus of cGAS. Compared with THP1 cells expressing wild-type cGAS, those expressing a mutant form of cGAS that did not associate with the plasma membrane (cGASΔN) showed increased basal IFN expression, exacerbated responses to genotoxic stress induced by H2O2, and reduced responses to infection with modified Vaccinia Ankara, a DNA virus. In the second paper, Dai et al. showed that basal acetylation of specific lysine residues keeps cGAS in an inactive state. Activation of cGAS required deacetylation of Lys384, Lys394, or Lys414 by HDAC3. Aspirin can directly acetylate various proteins. Aspirin treatment of THP1 cells, human peripheral blood mononuclear cells (PBMCs), or BMDMs resulted in the acetylation of cGAS and reduced production of cGAMP. Aicardi-Goutiѐres syndrome (AGS) patients have loss of function mutations in TREX1, which encodes an exonuclease that degrades cytosolic DNA. Aspirin treatment of Trex1–/–mice prevented the weight loss and decreased the ISG expression seen in untreated mice, and it also reduced ISG expression in PBMCs from an AGS patient. Thus, plasma membrane localization and acetylation are mechanisms that ensure that cGAS activation occurs at the right place and time.

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