Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS.
2',5'-Oligoadenylate Synthetase
/ genetics
Adaptor Proteins, Signal Transducing
/ genetics
Apoptosis Regulatory Proteins
/ genetics
Bloom Syndrome
/ pathology
Child
Cytosol
/ metabolism
DNA Damage
/ immunology
Exodeoxyribonucleases
/ metabolism
Fibroblasts
/ metabolism
HEK293 Cells
HeLa Cells
Humans
Immunity, Innate
/ immunology
Interferon Regulatory Factor-3
/ metabolism
Male
Membrane Proteins
/ metabolism
Nucleotidyltransferases
/ genetics
Phosphoproteins
/ metabolism
RNA-Binding Proteins
/ genetics
RecQ Helicases
/ genetics
Transcriptome
Transduction, Genetic
Tumor Suppressor Proteins
/ genetics
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:
06 05 2019
06 05 2019
Historique:
received:
13
07
2018
revised:
25
01
2019
accepted:
12
03
2019
pubmed:
3
4
2019
medline:
6
5
2020
entrez:
3
4
2019
Statut:
ppublish
Résumé
Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ-like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-stimulated gene (ISG) expression, which is mediated by the cGAS-STING-IRF3 cytosolic DNA-sensing pathway. Increased DNA damage or down-regulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BLM-deficient fibroblasts. cGAS-containing cytoplasmic micronuclei are increased in BS cells. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. These results reveal that BLM limits ISG induction, thus connecting DNA damage to cellular innate immune response, which may contribute to human pathogenesis.
Identifiants
pubmed: 30936263
pii: jem.20181329
doi: 10.1084/jem.20181329
pmc: PMC6504208
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Apoptosis Regulatory Proteins
0
IFI44L protein, human
0
IFIT1 protein, human
0
IFIT2 protein, human
0
IRF3 protein, human
0
Interferon Regulatory Factor-3
0
Membrane Proteins
0
Phosphoproteins
0
RNA-Binding Proteins
0
STING1 protein, human
0
Tumor Suppressor Proteins
0
Nucleotidyltransferases
EC 2.7.7.-
OAS1 protein, human
EC 2.7.7.-
cGAS protein, human
EC 2.7.7.-
2',5'-Oligoadenylate Synthetase
EC 2.7.7.84
Exodeoxyribonucleases
EC 3.1.-
three prime repair exonuclease 1
EC 3.1.16.-
Bloom syndrome protein
EC 3.6.1.-
RecQ Helicases
EC 3.6.4.12
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1199-1213Subventions
Organisme : Medical Research Council
ID : MR/M501803/1
Pays : United Kingdom
Informations de copyright
© 2019 Gratia et al.
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