A central role for PI3K-AKT signaling pathway in linking SAMHD1-deficiency to the type I interferon signature.
Sci Rep
; 8(1): 84, 2018 01 08.
Article
em En
| MEDLINE
| ID: mdl-29311560
ABSTRACT
The autoimmune disorder Aicardi-Goutières syndrome (AGS) is characterized by a constitutive type I interferon response. SAMHD1 possesses both dNTPase and RNase activities and mutations in SAMHD1 cause AGS; however, how SAMHD1-deficiency causes the type I interferon response in patients with AGS remains unknown. Here, we show that endogenous RNA substrates accumulated in the absence of SAMHD1 act as a major immunogenic source for the type I interferon response. Reconstitution of SAMHD1-negative human cells with wild-type but not RNase-defective SAMHD1 abolishes spontaneous type I interferon induction. We further identify that the PI3K/AKT/IRF3 signaling pathway is essential for the type I interferon response in SAMHD1-deficient human monocytic cells. Treatment of PI3K or AKT inhibitors dramatically reduces the type I interferon signatures in SAMHD1-deficient cells. Moreover, SAMHD1/AKT1 double knockout relieves the type I interferon signatures to the levels observed for wild-type cells. Identification of AGS-related RNA sensing pathway provides critical insights into the molecular pathogenesis of the type I interferonopathies such as AGS and overlapping autoimmune disorders.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Interferon Tipo I
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Fosfatidilinositol 3-Quinases
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Proteínas Proto-Oncogênicas c-akt
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Estudos de Associação Genética
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Proteína 1 com Domínio SAM e Domínio HD
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2018
Tipo de documento:
Article