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

Abstract

Nuclear factor-κB (NF-κB)-mediated inflammation is a major cause of acute respiratory distress syndrome (ARDS). However, the regulatory mechanisms by which NF-κB 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'-UTRs) of ataxin 1 (ATXN1), suppressing its expression. Decreased ATXN1 expression relieves its repression of NF-κB, 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-κB-dependent inflammatory response. Interfering with this signaling pathway to block the inflammatory response may be a strategy for treating ARDS. KEY MESSAGES : The transcription factor AP1 recruits p300 and CtBP1 to form a transcriptional complex, which transactivates the expression of hsa-miR-7-5p in ARDS biopsies. Overexpressed hsa-miR-7-5p binds to the 3'-UTR of ATXN1, suppressing its expression. The decreased ATXN1 impaired its suppression of NF-κB, causing the induction of proinflammatory cytokine genes and triggering inflammation response. Disruption of the assembly of CtBP2-p300-AP1 complex upregulates ATXN1 and attenuates inflammation.

Keywords: AP1; ARDS; ATXN1; CtBP1; Hsa-miR-7-5p; NF-κB.