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NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes
Injury or stress can induce intracellular translocation and release of nuclear HMGB1, a DAMP molecule known to participate in inflammation and other pathological processes. Active release of HMGB1 from stimulated macrophages can be mediated by inflammasomes, which cleave Gasdermin D to form pores on...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382497/ https://www.ncbi.nlm.nih.gov/pubmed/37507374 http://dx.doi.org/10.1038/s41420-023-01495-x |
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author | Khambu, Bilon Cai, Genxiang Liu, Gang Bailey, Niani Tiaye Mercer, Arissa A. Baral, Kamal Ma, Michelle Chen, Xiaoyun Li, Yu Yin, Xiao-Ming |
author_facet | Khambu, Bilon Cai, Genxiang Liu, Gang Bailey, Niani Tiaye Mercer, Arissa A. Baral, Kamal Ma, Michelle Chen, Xiaoyun Li, Yu Yin, Xiao-Ming |
author_sort | Khambu, Bilon |
collection | PubMed |
description | Injury or stress can induce intracellular translocation and release of nuclear HMGB1, a DAMP molecule known to participate in inflammation and other pathological processes. Active release of HMGB1 from stimulated macrophages can be mediated by inflammasomes, which cleave Gasdermin D to form pores on cytoplasmic membranes. We previously had shown that active release of HMGB1 from autophagy deficient hepatocytes also depended on the inflammasome but how the inflammasome was activated was not known. Here we report that persistent activation of transcription factor NRF2 under the autophagy deficient condition led to transcriptional upregulation of Caspase-11 expression, which could then activate the CASPASE-1inflammasome. Using chromatin immunoprecipitation (CHIP) and luciferase-based reporter assays, we show that NRF2 directly binds to the Caspase-11 promoter and transcriptionally increase the expression of Caspase-11. Genetic deletion of Caspase-11 in autophagy-deficient livers represses the release of HMGB1 and its pathological consequence, ductular cell proliferation. Consistently, deletion of NLRP3, which can activate CASPASE-1 mediated inflammasomes under other types of signals, did not prevent HMGB1 release and ductular cell proliferation in autophagy deficient livers. Surprisingly, while cleavage of GASDEMIN D occurred in autophagy-deficient livers its deletion did not prevent the HMGB1 release, suggesting that CASPASE-11-mediated inflammasome activation may also engage in a different mechanism for HMGB1 release by the autophagy deficient hepatocytes. Collectively, this work reveals the novel role of NRF2 in transcriptional upregulation of Caspase-11 and in inflammasome activation to promote active release of HMGB via a non-Gasdermin D mediated avenue. |
format | Online Article Text |
id | pubmed-10382497 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103824972023-07-30 NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes Khambu, Bilon Cai, Genxiang Liu, Gang Bailey, Niani Tiaye Mercer, Arissa A. Baral, Kamal Ma, Michelle Chen, Xiaoyun Li, Yu Yin, Xiao-Ming Cell Death Discov Article Injury or stress can induce intracellular translocation and release of nuclear HMGB1, a DAMP molecule known to participate in inflammation and other pathological processes. Active release of HMGB1 from stimulated macrophages can be mediated by inflammasomes, which cleave Gasdermin D to form pores on cytoplasmic membranes. We previously had shown that active release of HMGB1 from autophagy deficient hepatocytes also depended on the inflammasome but how the inflammasome was activated was not known. Here we report that persistent activation of transcription factor NRF2 under the autophagy deficient condition led to transcriptional upregulation of Caspase-11 expression, which could then activate the CASPASE-1inflammasome. Using chromatin immunoprecipitation (CHIP) and luciferase-based reporter assays, we show that NRF2 directly binds to the Caspase-11 promoter and transcriptionally increase the expression of Caspase-11. Genetic deletion of Caspase-11 in autophagy-deficient livers represses the release of HMGB1 and its pathological consequence, ductular cell proliferation. Consistently, deletion of NLRP3, which can activate CASPASE-1 mediated inflammasomes under other types of signals, did not prevent HMGB1 release and ductular cell proliferation in autophagy deficient livers. Surprisingly, while cleavage of GASDEMIN D occurred in autophagy-deficient livers its deletion did not prevent the HMGB1 release, suggesting that CASPASE-11-mediated inflammasome activation may also engage in a different mechanism for HMGB1 release by the autophagy deficient hepatocytes. Collectively, this work reveals the novel role of NRF2 in transcriptional upregulation of Caspase-11 and in inflammasome activation to promote active release of HMGB via a non-Gasdermin D mediated avenue. Nature Publishing Group UK 2023-07-28 /pmc/articles/PMC10382497/ /pubmed/37507374 http://dx.doi.org/10.1038/s41420-023-01495-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Khambu, Bilon Cai, Genxiang Liu, Gang Bailey, Niani Tiaye Mercer, Arissa A. Baral, Kamal Ma, Michelle Chen, Xiaoyun Li, Yu Yin, Xiao-Ming NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes |
title | NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes |
title_full | NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes |
title_fullStr | NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes |
title_full_unstemmed | NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes |
title_short | NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes |
title_sort | nrf2 transcriptionally regulates caspase-11 expression to activate hmgb1 release by autophagy-deficient hepatocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382497/ https://www.ncbi.nlm.nih.gov/pubmed/37507374 http://dx.doi.org/10.1038/s41420-023-01495-x |
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