Mechanism of RNA m6 A methylation modification regulating NLRP3 inflammasome activation for hand, foot, and mouth disease progression.
J Med Virol
; 95(7): e28939, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37409616
ABSTRACT
Some children infected with hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) progressed to severe disease with various neurological complications in the short term, with a poor prognosis and high mortality. Studies had revealed that RNA N6 -methyladenosine (m6 A) modification had a significant impact on EV71 replication, but it was unknown how m6 A modification regulated the host cell's innate immune response brought on by EV71 infection. We used MeRIP-seq (methylation RNA immunoprecipitation sequencing), RNA-seq (RNA sequencing), cell transfection, and other techniques. MeRIP-seq and RNA-seq results showed the m6 A methylation modification map of control and EV71-infected groups of RD cells. And multilevel validation indicated that decreased expression of demethylase FTO (fat mass and obesity-associated protein) was responsible for the elevated total m6 A modification levels in EV71-infected RD cells and that thioredoxin interacting protein (TXNIP) may be a target gene for demethylase FTO action. Further functional experiments showed that demethylase knockdown of FTO promoted TXNIP expression, activation of NLRP3 inflammasome and promoted the release of proinflammatory factors in vitro, and the opposite result occurred with demethylase FTO overexpression. And further tested in an animal model of EV71 infection in vitro, with results consistent with in vitro. Our findings elucidated that depletion of the demethylase FTO during EV71 infection increased the m6 A modification level of TXNIP mRNA 3' untranslated region (UTR), enhancing mRNA stability, and promoting TXNIP expression. Consequently, the NLRP3 inflammasome was stimulated, leading to the release of proinflammatory factors and facilitating HFMD progression.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Enterovirus
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Enterovirus Humano A
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Infecções por Enterovirus
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Doença de Mão, Pé e Boca
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Med Virol
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China