Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
02 01 2023
02 01 2023
Historique:
received:
11
05
2022
revised:
01
09
2022
accepted:
06
10
2022
entrez:
8
11
2022
pubmed:
9
11
2022
medline:
11
11
2022
Statut:
ppublish
Résumé
Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon-driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.
Identifiants
pubmed: 36346347
pii: 213670
doi: 10.1084/jem.20220829
pmc: PMC9648672
pii:
doi:
Substances chimiques
SAM Domain and HD Domain-Containing Protein 1
EC 3.1.5.-
Membrane Proteins
0
Nucleotidyltransferases
EC 2.7.7.-
Interferon Type I
0
Nucleic Acids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2022 Schumann et al.
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