Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.
J Exp Med
; 218(10)2021 10 04.
Article
in En
| MEDLINE
| ID: mdl-34387651
ABSTRACT
Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interferons
/
Mitochondrial Proteins
/
ATPases Associated with Diverse Cellular Activities
/
Membrane Proteins
/
Mutation
/
Nucleotidyltransferases
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Language:
En
Journal:
J Exp Med
Year:
2021
Document type:
Article
Affiliation country: