The methyl-CpG-binding protein 2 inhibits cGAS-associated signaling.

The detection of cytosolic dsDNA by the cyclic GMP-AMP synthase (cGAS) is tightly regulated to avoid pathological inflammatory responses. Here, we show that the methyl-CpG-binding protein 2 (MeCP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. The presence of cytosolic dsDNA promotes MeCP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening detection by cGAS. MeCP2 export partially phenocopies MeCP2 deficiency, leading to innate immune activation and enforcing an antiviral state. Finally, MeCP2 displacement from the nucleus following dsDNA stimulation disrupts its canonical function, leading to the reactivation of otherwise repressed genes, such as endogenous retroelements. Re-expression of the latter leads to the accumulation of DNA species feeding cGAS-dependent signalling. We thus establish a direct role of MeCP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses and suggest targeting dsDNA-associated pathways or endogenous retroelements as therapeutic options for patients with MeCP2 deficiency.