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SARS-CoV-2 papain-like protease inhibits IL-1β maturation and pyroptosis through disruption of ASC oligomerization and deubiquitination of ASC
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  • Huan Meng,
  • Jianglin Zhou,
  • Xiaojuan Chen,
  • MingYu Wang,
  • Mei Zheng,
  • Yunhui Li,
  • Ying Han,
  • Jin Chen,
  • Jinyu Han,
  • Jing Liang,
  • Yaling Xing,
  • Yajie Wang
Huan Meng
Capital Medical University
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Jianglin Zhou
Beijing Institute of Microbiology and Epidemiology
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Xiaojuan Chen
Beijing Institute of Microbiology and Epidemiology
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MingYu Wang
Beijing Institute of Microbiology and Epidemiology
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Mei Zheng
Capital Medical University
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Yunhui Li
Capital Medical University
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Ying Han
Capital Medical University
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Jin Chen
Capital Medical University
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Jinyu Han
Capital Medical University
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Jing Liang
Capital Medical University
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Yaling Xing
Beijing Institute of Microbiology and Epidemiology
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Yajie Wang
Capital Medical University

Corresponding Author:wangyajie@ccmu.edu.cn

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Abstract

The perplexing innate immune response induced by SARS-CoV-2 infection remains inadequate uncovered. Previous studies showed that coronavirus papain-like protease (PLP) could evade type I interferons mediated innate immune responses. In this study, we found the inflammasome genes (NLRP3, NLRP6, PYCARD, IL1B, IL18, TRIM31, FBXL2, MARCH7) were down-regulated in CD14+ monocytes from COVID-19 patients. Secondly, we found that SARS-CoV-2 PLP may act on the NLRP3 inflammasome pathway. PLP may interact with ASC and interrupt ASC oligomerization by reducing the K48-linked and K63-linked ubiquitination of ASC, so that the excessive activation of the NLRP3 inflammatory pathway might be inhibited and the release of IL-1β was blocked. Thirdly, SARS-CoV-2 PLP negatively regulated the pyroptosis of host cells, which was mediated by caspase-1, the key regulator of the NLRP3 inflammasome pathway. In general, SARS-CoV-2 PLP avoids the excessive immune defenses in the early stage of virus infection, which provides the maximum advantage for virus replication. These insights uncover the flex function of CoV encoding proteases. Furthermore, this research may provide a new vision of COVID-19 epidemic prevention and new possibilities for new therapies.
23 Jan 2023Submitted to Journal of Medical Virology
24 Jan 2023Assigned to Editor
24 Jan 2023Submission Checks Completed
24 Jan 2023Review(s) Completed, Editorial Evaluation Pending
27 Jan 2023Reviewer(s) Assigned