Elevation of hsa-miR-7-5p level mediated by CtBP1-p300-AP1 complex targets ATXN1 to trigger NF-?B-dependent inflammation response

Nuclear factor-kappa B (NF-kappa B)-mediated inflammation is a major cause of acute respiratory distress syndrome (ARDS). However, the regulatory mechanisms by which NF-kappa B transactivates proinflammatory cytokines remain unclear in the pathogenesis of ARDS. Herein, we report that the activating protein 1 (AP1) transcription factor recruits a histone acetyltransferase p300 and a transcriptional regulator C-terminal binding protein 1 (CtBP1) to assemble the CtBP1-p300-AP1 complex, which transactivates the expression of hsa-miR-7-5p in ARDS biopsies. Overexpressed hsa-miR-7-5p binds to the three prime untranslated regions (3 & PRIME;-UTRs) of ataxin 1 (ATXN1), suppressing its expression. Decreased ATXN1 expression relieves its repression of NF-kappa B, causing the induction of proinflammatory cytokine genes and triggering an inflammatory response. Depletion of CtBP1 or treatments with two CtBP1 inhibitors (NSC95397 and 4-methylthio-2-oxobutanoate (MTOB)) in human macrophages impairs the assembly of the CtBP2-p300-AP1 complex, resulting in decreased hsa-miR-7-5p levels, upregulation of ATXN1, and attenuation of proinflammatory cytokines. A similar regulatory mechanism was observed in lipopolysaccharide-treated mice. Our results reveal that increased hsa-miR-7-5p level mediated by the CtBP1-p300-AP1 complex targets ATXN1 to trigger an NF-kappa B-dependent inflammatory response. Interfering with this signaling pathway to block the inflammatory response may be a strategy for treating ARDS.

Automated summary

In this study, it was found that the AP1 transcription factor recruits p300 histone acetyltransferase and CtBP1 to form the CtBP1-p300-AP1 complex, which transactivates hsa-miR-7-5p expression in ARDS biopsies. Hsa-miR-7-5p targets ATXN1 to trigger an NF-kappa B-dependent inflammatory response. Interfering with the CtBP1-p300-AP1 signaling pathway may be a potential strategy for treating ARDS.