N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1.
J Exp Med
; 215(10): 2600-2616, 2018 10 01.
Article
em En
| MEDLINE
| ID: mdl-30135079
ABSTRACT
Mutations in the NGLY1 (N-glycanase 1) gene, encoding an evolutionarily conserved deglycosylation enzyme, are associated with a rare congenital disorder leading to global developmental delay and neurological abnormalities. The molecular mechanism of the NGLY1 disease and its function in tissue and immune homeostasis remain unknown. Here, we find that NGLY1-deficient human and mouse cells chronically activate cytosolic nucleic acid-sensing pathways, leading to elevated interferon gene signature. We also find that cellular clearance of damaged mitochondria by mitophagy is impaired in the absence of NGLY1, resulting in severely fragmented mitochondria and activation of cGAS-STING as well as MDA5-MAVS pathways. Furthermore, we show that NGLY1 regulates mitochondrial homeostasis through transcriptional factor NRF1. Remarkably, pharmacological activation of a homologous but nonglycosylated transcriptional factor NRF2 restores mitochondrial homeostasis and suppresses immune gene activation in NGLY1-deficient cells. Together, our findings reveal novel functions of the NGLY1-NRF1 pathway in mitochondrial homeostasis and inflammation and uncover an unexpected therapeutic strategy using pharmacological activators of NRF2 for treating mitochondrial and immune dysregulation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Defeitos Congênitos da Glicosilação
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Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase
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Fator 1 Relacionado a NF-E2
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Homeostase
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Mitocôndrias
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2018
Tipo de documento:
Article