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

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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.

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Data Availability

The date sets used and analyzed during the current study are available from the corresponding author upon request.

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Funding

This study was supported by a grant (20212BAB206057, assigned to Dr. Zhi Chen) from the Natural Science Foundation of Jiangxi Province, China.

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Authors and Affiliations

  1. Central Supply Service Department, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China

    Li-Qiong Lou

  2. Medical Department of Graduate School, Nanchang University, Nanchang, 330006, Jiangxi, China

    Wen-Qiang Zhou & Xin Song

  3. Department of Emergency, Donghu District, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, 92 Aiguo Rd, Nanchang, 330006, Jiangxi, China

    Wen-Qiang Zhou, Xin Song & Zhi Chen

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  1. Li-Qiong Lou
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  2. Wen-Qiang Zhou
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  3. Xin Song
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  4. Zhi Chen
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Contributions

Dr. Li-Qiong Lou and Dr. Zhi Chen designed the experiments and wrote the manuscript. Dr. Zhi Chen performed the major parts of the experiments (detection of microRNA and gene expression levels, western blots, Co-IP, IP, and ChIP). Wen-Qiang Zhou and Xin Song helped cell culture, constructed vectors, and generated cell lines.

Corresponding author

Correspondence to Zhi Chen.

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Ethics approval and consent to participate

The animal experiments were performed in accordance with a protocol (ARDS202111-2) reviewed and approved by the Institutional Animal Care and Use Committee of Jiangxi Provincial Hospital. The human lung tissue collection and BAL fluid collection were performed following a protocol (ARDS20091B) reviewed and approved by the Ethics Committee of Jiangxi Provincial People’s Hospital. All participants signed the written consent reviewed and approved by the Ethics Committee of Jiangxi Provincial People’s Hospital.

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The authors declare no competing interests.

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Lou, LQ., Zhou, WQ., Song, X. et al. Elevation of hsa-miR-7-5p level mediated by CtBP1-p300-AP1 complex targets ATXN1 to trigger NF-κB-dependent inflammation response. J Mol Med 101, 223–235 (2023). https://doi.org/10.1007/s00109-022-02274-4

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  • DOI: https://doi.org/10.1007/s00109-022-02274-4

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