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Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1.
Chen, Zhi; Dong, Wei-Hua; Chen, Qiang; Li, Qiu-Gen; Qiu, Zhong-Min.
Afiliação
  • Chen Z; Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
  • Dong WH; Department of Critical Care Medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, Jiangxi, China.
  • Chen Q; Department of Critical Care Medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, Jiangxi, China.
  • Li QG; Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
  • Qiu ZM; Department of Pulmonary and Critical Care Medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, Jiangxi, China.
Int J Biol Sci ; 15(12): 2627-2640, 2019.
Article em En | MEDLINE | ID: mdl-31754335
Emerging evidence indicates that microRNAs (miRNAs) play fundamental roles in the pathogenesis of multiple diseases, including acute lung injury (ALI). Here, we discovered that miR-199a-3p was significantly downregulated in ALI lung tissues using a microarray analysis. In vitro lipopolysaccharide (LPS) treatment of the human epithelial cell line A549 and the human macrophage cell line U937 caused a decrease of miR-199a-3p. Mechanically, miR-199a-3p specifically bound to the 3'-untranslated region (3'-UTR) of NLRP1 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 1), a critical member of inflammasomes. Ectopic overexpression or downregulation of miR-199a-3p resulted in the repression or induction of NLRP1, respectively, thereby downregulating or activating its downstream events. Moreover, transcription factor FOXP3 (forkhead box P3) was able to specifically bind to the promoter of miR-199a-3p. Knockdown or overexpression of FOXP3 resulted in a decrease or induction miR-199a-3p expression, respectively. Using immunoprecipitation (IP), mass spectrometry and co-IP assays, we found that FOXP3 formed a transcriptional complex with HDAC1 (histone deacetylase 1) and CtBP2 (C-terminal-binding protein 2). Collectively, our results suggested that the CtBP2-HDAC1-FOXP3 transcriptional complex (CHFTC) could specifically bind to the promoter of miR-199a-3p and repress its expression. Downregulation of miR-199a-3p eliminated its inhibition of NLRP1, causing activation of NLRP1 and cleavage of pro-IL-1ß and pro-IL-18 mediated by Caspase-1. The secretion of IL-1ß and IL-18 further aggravated the inflammatory response and resulted in the occurrence of ALI.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Lipopolissacarídeos / MicroRNAs / Lesão Pulmonar Aguda Limite: Humans Idioma: En Revista: Int J Biol Sci Assunto da revista: BIOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: China País de publicação: Austrália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Lipopolissacarídeos / MicroRNAs / Lesão Pulmonar Aguda Limite: Humans Idioma: En Revista: Int J Biol Sci Assunto da revista: BIOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: China País de publicação: Austrália