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

Hanane Chamma, Soumyabrata Guha, Roger Junior Eloiflin, Adeline Augereau, Pierre Le Hars, Moritz Schüssler, Yasmine Messaoud-Nacer, Mohammad Salma, Joe McKellar, Joanna Re, Morgane Chemarin, Arnaud Carrier, Michael A. Disyak, Clara Taffoni, Robin Charpentier, Zoé Husson, Emmanuel Valjent, Charlotte Andrieu-Soler, Eric Soler, Maria H. Christensen, Søren R. Paludan, Florian I. Schmidt, Daniela Tropea, Karim Majzoub, Isabelle K. Vila and Nadine Laguette ()
Additional contact information
Hanane Chamma: Université de Montpellier
Soumyabrata Guha: Université de Montpellier
Roger Junior Eloiflin: Université de Montpellier
Adeline Augereau: Université de Montpellier
Pierre Le Hars: Université de Montpellier
Moritz Schüssler: Université de Montpellier
Yasmine Messaoud-Nacer: Université de Montpellier
Mohammad Salma: Université de Montpellier
Joe McKellar: Université de Montpellier
Joanna Re: Université de Montpellier
Morgane Chemarin: Université de Montpellier
Arnaud Carrier: Université de Montpellier
Michael A. Disyak: Université de Montpellier
Clara Taffoni: Université de Montpellier
Robin Charpentier: Université de Montpellier
Zoé Husson: Université de Montpelier
Emmanuel Valjent: Université de Montpellier
Charlotte Andrieu-Soler: Université de Montpellier
Eric Soler: Université de Montpellier
Maria H. Christensen: University of Bonn
Søren R. Paludan: Aarhus University
Florian I. Schmidt: University of Bonn
Daniela Tropea: St James Hospital
Karim Majzoub: Université de Montpellier
Isabelle K. Vila: Université de Montpellier
Nadine Laguette: Université de Montpellier

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65713-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65713-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65713-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().