Succination inactivates gasdermin D and blocks pyroptosis.
Science
; 369(6511): 1633-1637, 2020 09 25.
Article
em En
| MEDLINE
| ID: mdl-32820063
ABSTRACT
Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Febre Familiar do Mediterrâneo
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Cisteína
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Proteínas de Ligação a Fosfato
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Peptídeos e Proteínas de Sinalização Intracelular
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Encefalomielite Autoimune Experimental
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Fumarato de Dimetilo
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Piroptose
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Esclerose Múltipla
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Science
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos