Editors' ChoiceImmunology

Keeping cGAS under control

Sci. Signal.  05 Apr 2016:
Vol. 9, Issue 422, pp. ec78
DOI: 10.1126/scisignal.aaf8044

The cytosolic enzyme cyclic GMP-AMP (cGAMP) synthase (cGAS) is a sensor of cytosolic double-stranded DNA, both pathogenic and self. Upon activation by binding to DNA, cGAS synthesizes cGAMP, which binds to the endoplasmic reticulum–resident adaptor protein STING. The activation of STING in turn stimulates the production of type I interferon (IFN) as part of the antiviral immune response. Glutamylation is a posttranslational modification that is catalyzed by tubulin tyrosine ligase-like (TTLL) glutamylases and is reversed by members of the cytosolic carboxypeptidase (CCP) family of enzymes. Xia et al. found that, compared with wild-type mice, mice deficient in either CCP5 or CCP6 were more susceptible to infection with DNA viruses, which was associated with decreased activation of the transcription factor IRF3 in bone marrow–derived macrophages (BMDMs) and dendritic cells (DCs) and reduced production of type I IFN. Analysis of BMDM lysates by affinity chromatography and mass spectrometry showed that cGAS was a CCP substrate, and mutational analysis showed that CCP5 hydrolyzed the glutamate chain at Glu302, whereas CCP6 hydrolyzed the glutamate chain at Glu272. The monoglutamylase TTL4 and the polyglutamylase TTL6 associated with cGAS in BMDMs. Mutational analysis revealed that polyglutamylation of Glu272 blocked cGAS from binding to double-stranded DNA, whereas monoglutamylation of Glu272 prevented cGAS from synthesizing cGAMP. Thus, BMDMs from mice deficient in both CCP5 and CCP6 exhibited enhanced cGAS glutamylation, were more susceptible than singly deficient mice to DNA virus infection, and produced less type I IFN. In contrast, BMDMs from mice deficient in both TTL4 and TTL6 lacked glutamylation of cGAS, produced more type I IFN than did singly deficient mice, and were more resistant to DNA virus infection. As Ablasser discusses in the associated commentary, the finding that cGAS function is reversibly regulated by glutamylation raises the question of how the enzymes involved are regulated.

P. Xia, B. Ye, S. Wang, X. Zhu, Y. Du, Z. Xiong, Y. Tian, Z. Fan, Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat. Immunol. 17, 369–378 (2016). [PubMed]

A. Ablasser, ReGLUation of cGAS. Nat. Immunol. 17, 347–349 (2016). [PubMed]