Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

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Lepelley , A , Della Mina , E , Van Nieuwenhove , E , Waumans , L , Fraitag , S , Rice , G I , Dhir , A , Fremond , M-L , Rodero , M P , Seabra , L , Carter , E , Bodemer , C , Buhas , D , Callewaert , B , de Lonlay , P , De Somer , L , Dyment , D A , Faes , F , Grove , L , Holden , S , Hully , M , Kurian , M A , McMillan , H J , Suetens , K , Tyynismaa , H , Chhun , S , Wai , T , Wouters , C , Bader-Meunier , B & Crow , Y J 2021 , ' Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A ' , Journal of Experimental Medicine , vol. 218 , no. 10 , 20201560 . https://doi.org/10.1084/jem.20201560

Titel: Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A
Författare: Lepelley, Alice; Della Mina, Erika; Van Nieuwenhove, Erika; Waumans, Lise; Fraitag, Sylvie; Rice, Gillian I.; Dhir, Ashish; Fremond, Marie-Louise; Rodero, Mathieu P.; Seabra, Luis; Carter, Edwin; Bodemer, Christine; Buhas, Daniela; Callewaert, Bert; de Lonlay, Pascale; De Somer, Lien; Dyment, David A.; Faes, Fran; Grove, Lucy; Holden, Simon; Hully, Marie; Kurian, Manju A.; McMillan, Hugh J.; Suetens, Kristin; Tyynismaa, Henna; Chhun, Stephanie; Wai, Timothy; Wouters, Carine; Bader-Meunier, Brigitte; Crow, Yanick J.
Upphovmannens organisation: STEMM - Stem Cells and Metabolism Research Program
Centre of Excellence in Stem Cell Metabolism
Staff Services
Henna Tyynismaa / Principal Investigator
Neuroscience Center
Helsinki Institute of Life Science HiLIFE
Datum: 2021-10-04
Språk: eng
Sidantal: 23
Tillhör serie: Journal of Experimental Medicine
ISSN: 0022-1007
DOI: https://doi.org/10.1084/jem.20201560
Permanenta länken (URI): http://hdl.handle.net/10138/336598
Abstrakt: 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 alpha 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.
Subject: RECURRENT DE-NOVO
AICARDI-GOUTIERES SYNDROME
MITOCHONDRIAL-DNA
I INTERFERON
MEMBRANE-PROTEIN
RNASEH2B
DUPLICATIONS
CHOLESTEROL
DYSFUNCTION
INDUCTION
3111 Biomedicine
Referentgranskad: Ja
Licens: cc_by_nc_sa
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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