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BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation
INTRODUCTION: Inflammation play important roles in the initiation and progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), septic shock, clotting dysfunction, or even death associated with SARS-CoV-2 infection. However, the pathogenic mechanisms underlying SARS-CoV-2-i...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10019892/ https://www.ncbi.nlm.nih.gov/pubmed/36936774 http://dx.doi.org/10.3389/fcimb.2023.1134511 |
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author | Li, Jingfei Lin, Haotian Fan, Tinghui Huang, Linfei Zhang, Xinyong Tai, Yanhong Fang, Yi Li, Qihong Zhao, Ruzhou Wang, Penghao Zhou, Li Wan, Luming Wu, Yuhua Zhong, Hui Wei, Congwen Yang, Xiaopan |
author_facet | Li, Jingfei Lin, Haotian Fan, Tinghui Huang, Linfei Zhang, Xinyong Tai, Yanhong Fang, Yi Li, Qihong Zhao, Ruzhou Wang, Penghao Zhou, Li Wan, Luming Wu, Yuhua Zhong, Hui Wei, Congwen Yang, Xiaopan |
author_sort | Li, Jingfei |
collection | PubMed |
description | INTRODUCTION: Inflammation play important roles in the initiation and progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), septic shock, clotting dysfunction, or even death associated with SARS-CoV-2 infection. However, the pathogenic mechanisms underlying SARS-CoV-2-induced hyperinflammation are still largely unknown. METHODS: The animal model of septic shock and ALI was established after LPS intraperitoneal injection or intratracheal instillation. Bone marrow-derived macrophages (BMDMs) from WT and BPOZ-2 KO mouse strains were harvested from the femurs and tibias of mice. Immunohistology staining, ELISA assay, coimmunoprecipitation, and immunoblot analysis were used to detect the histopathological changes of lung tissues and the expression of inflammatory factors and protein interaction. RESULTS AND CONCLUSIONS: We show a distinct mechanism by which the SARS-CoV-2 N (SARS-2-N) protein targets Bood POZ-containing gene type 2 (BPOZ-2), a scaffold protein for the E3 ubiquitin ligase Cullin 3 that we identified as a negative regulator of inflammatory responses, to promote NLRP3 inflammasome activation. We first demonstrated that BPOZ-2 knockout (BPOZ-2 KO) mice were more susceptible to lipopolysaccharide (LPS)-induced septic shock and ALI and showed increased serum IL-1β levels. In addition, BMDMs isolated from BPOZ-2 KO mice showed increased IL-1β production in response to NLRP3 stimuli. Mechanistically, BPOZ-2 interacted with NLRP3 and mediated its degradation by recruiting Cullin 3. In particular, the expression of BPOZ-2 was significantly reduced in lung tissues from mice infected with SARS-CoV-2 and in cells overexpressing SARS-2-N. Importantly, proinflammatory responses triggered by the SARS-2-N were significantly blocked by BPOZ-2 reintroduction. Thus, we concluded that BPOZ-2 is a negative regulator of the NLPR3 inflammasome that likely contributes to SARS-CoV-2-induced hyperinflammation. |
format | Online Article Text |
id | pubmed-10019892 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100198922023-03-17 BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation Li, Jingfei Lin, Haotian Fan, Tinghui Huang, Linfei Zhang, Xinyong Tai, Yanhong Fang, Yi Li, Qihong Zhao, Ruzhou Wang, Penghao Zhou, Li Wan, Luming Wu, Yuhua Zhong, Hui Wei, Congwen Yang, Xiaopan Front Cell Infect Microbiol Cellular and Infection Microbiology INTRODUCTION: Inflammation play important roles in the initiation and progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), septic shock, clotting dysfunction, or even death associated with SARS-CoV-2 infection. However, the pathogenic mechanisms underlying SARS-CoV-2-induced hyperinflammation are still largely unknown. METHODS: The animal model of septic shock and ALI was established after LPS intraperitoneal injection or intratracheal instillation. Bone marrow-derived macrophages (BMDMs) from WT and BPOZ-2 KO mouse strains were harvested from the femurs and tibias of mice. Immunohistology staining, ELISA assay, coimmunoprecipitation, and immunoblot analysis were used to detect the histopathological changes of lung tissues and the expression of inflammatory factors and protein interaction. RESULTS AND CONCLUSIONS: We show a distinct mechanism by which the SARS-CoV-2 N (SARS-2-N) protein targets Bood POZ-containing gene type 2 (BPOZ-2), a scaffold protein for the E3 ubiquitin ligase Cullin 3 that we identified as a negative regulator of inflammatory responses, to promote NLRP3 inflammasome activation. We first demonstrated that BPOZ-2 knockout (BPOZ-2 KO) mice were more susceptible to lipopolysaccharide (LPS)-induced septic shock and ALI and showed increased serum IL-1β levels. In addition, BMDMs isolated from BPOZ-2 KO mice showed increased IL-1β production in response to NLRP3 stimuli. Mechanistically, BPOZ-2 interacted with NLRP3 and mediated its degradation by recruiting Cullin 3. In particular, the expression of BPOZ-2 was significantly reduced in lung tissues from mice infected with SARS-CoV-2 and in cells overexpressing SARS-2-N. Importantly, proinflammatory responses triggered by the SARS-2-N were significantly blocked by BPOZ-2 reintroduction. Thus, we concluded that BPOZ-2 is a negative regulator of the NLPR3 inflammasome that likely contributes to SARS-CoV-2-induced hyperinflammation. Frontiers Media S.A. 2023-03-02 /pmc/articles/PMC10019892/ /pubmed/36936774 http://dx.doi.org/10.3389/fcimb.2023.1134511 Text en Copyright © 2023 Li, Lin, Fan, Huang, Zhang, Tai, Fang, Li, Zhao, Wang, Zhou, Wan, Wu, Zhong, Wei and Yang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular and Infection Microbiology Li, Jingfei Lin, Haotian Fan, Tinghui Huang, Linfei Zhang, Xinyong Tai, Yanhong Fang, Yi Li, Qihong Zhao, Ruzhou Wang, Penghao Zhou, Li Wan, Luming Wu, Yuhua Zhong, Hui Wei, Congwen Yang, Xiaopan BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation |
title | BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation |
title_full | BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation |
title_fullStr | BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation |
title_full_unstemmed | BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation |
title_short | BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation |
title_sort | bpoz-2 is a negative regulator of the nlpr3 inflammasome contributing to sars-cov-2-induced hyperinflammation |
topic | Cellular and Infection Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10019892/ https://www.ncbi.nlm.nih.gov/pubmed/36936774 http://dx.doi.org/10.3389/fcimb.2023.1134511 |
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