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CBX4 regulates long-form thymic stromal lymphopoietin-mediated airway inflammation through SUMOylation in HDM-induced asthma

Shixiu Liang, Zicong Zhou, Zili Zhou, Jieyi Liu, Hangming Dong, Fei Zou, Haijin Zhao, Changhui Yu, View ORCID ProfileShaoxi Cai
doi: https://doi.org/10.1101/2021.05.24.445396
Shixiu Liang
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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Zicong Zhou
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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Zili Zhou
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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Jieyi Liu
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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Hangming Dong
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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Fei Zou
2Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
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Haijin Zhao
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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  • For correspondence: caishaox@fimmu.com ych1029@i.smu.cn zhjin@fimmu.com
Changhui Yu
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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  • For correspondence: caishaox@fimmu.com ych1029@i.smu.cn zhjin@fimmu.com
Shaoxi Cai
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University
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  • ORCID record for Shaoxi Cai
  • For correspondence: caishaox@fimmu.com ych1029@i.smu.cn zhjin@fimmu.com
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Abstract

Rationale Thymic stromal lymphopoietin (TSLP) is present in two distinct isoforms, short-form (sfTSLP) and long-form (lfTSLP). lfTSLP promotes inflammation while sfTSLP inhibits inflammation in allergic asthma. However, little is known about the regulation of lfTSLP and sfTSLP during allergic attack in asthma airway epithelium.

Methods and Results Here, we report that SUMOylation was enhanced in HDM-induced allergic asthma airway epithelium. Inhibition of SUMOylation significantly alleviated airway Th2 inflammation and lfTSLP expression. Mechanistically, CBX4, a SUMOylation E3 ligase, enhanced lfTSLP, but not sfTSLP, mRNA translation through the RNA binding protein, MEX-3B. MEX-3B promoted lfTSLP translation through binding of its KH domains to the lfTSLP mRNA. Furthermore, CBX4 regulated MEX-3B transcription in HBE through enhancing SUMOylation levels of the transcription factor, TFII-I.

Conclusion We demonstrate an important mechanism whereby CBX4 promotes MEX-3B transcription through enhancing TFII-I SUMOylation, and MEX-3B enhances the expression of lfTSLP through binding to the lfTSLP mRNA and promoting its translation. Our findings uncover a novel target of CBX4 for therapeutic agents to lfTSLP-mediated asthma.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    CBX4
    chromobox 4
    HDM
    house dust mite
    lfTSLP
    long-form thymic stromal lymphopoietin
    SUMO1
    Small Ubiquitin Like Modifier 1.
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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    Posted May 26, 2021.
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    CBX4 regulates long-form thymic stromal lymphopoietin-mediated airway inflammation through SUMOylation in HDM-induced asthma
    Shixiu Liang, Zicong Zhou, Zili Zhou, Jieyi Liu, Hangming Dong, Fei Zou, Haijin Zhao, Changhui Yu, Shaoxi Cai
    bioRxiv 2021.05.24.445396; doi: https://doi.org/10.1101/2021.05.24.445396
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    CBX4 regulates long-form thymic stromal lymphopoietin-mediated airway inflammation through SUMOylation in HDM-induced asthma
    Shixiu Liang, Zicong Zhou, Zili Zhou, Jieyi Liu, Hangming Dong, Fei Zou, Haijin Zhao, Changhui Yu, Shaoxi Cai
    bioRxiv 2021.05.24.445396; doi: https://doi.org/10.1101/2021.05.24.445396

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