Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | https://repositorio.unifesp.br/handle/11600/55124 http://dx.doi.org/10.1038/srep41686 |
Resumo: | Nitric oxide synthase 2, inducible (Nos2) expression is necessary for the microbicidal activity of macrophages. However, NOS2 over-activation causes multiple inflammatory disorders, suggesting a tight gene regulation is necessary. Using cytosolic flagellin as a model for inflammasome-dependent NOS2 activation, we discovered a surprising new role for NLRC4/caspase-1 axis in regulating chromatin accessibility of the Nos2 promoter. We found that activation of two independent mechanisms is necessary for NOS2 expression by cytosolic flagellin: caspase-1 and NF-kappa B activation. NF-kappa B activation was necessary, but not sufficient, for NOS2 expression. Conversely, caspase-1 was necessary for NOS2 expression, but dispensable for NF-kappa B activation, indicating that this protease acts downstream NF-kappa B activation. We demonstrated that epigenetic regulation of Nos2 by caspase-1 involves cleavage of the chromatin regulator PARP1 (also known as ARTD1) and chromatin accessibility of the NF-kappa B binding sites located at the Nos2 promoter. Remarkably, caspase-1-mediated Nos2 transcription and NO production contribute to the resistance of macrophages to Salmonella typhimurium infection. Our results uncover the molecular mechanism behind the constricted regulation of Nos2 expression and open new therapeutic opportunities based on epigenetic activities of caspase-1 against infectious and inflammatory diseases. |
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Buzzo, Carina de Lima [UNIFESP]Medina, TiagoBranco, Laura M. [UNIFESP]Lage, Silvia L. [UNIFESP]de Souza Ferreira, Luis CarlosAmarante-Mendes, Gustavo P.Hottiger, Michael O.De Carvalho, Daniel D.Bortoluci, Karina R. [UNIFESP]2020-07-17T14:03:00Z2020-07-17T14:03:00Z2017Scientific Reports. London, v. 7, p. -, 2017.2045-2322https://repositorio.unifesp.br/handle/11600/55124http://dx.doi.org/10.1038/srep41686WOS000393651700001.pdf10.1038/srep41686WOS:000393651700001Nitric oxide synthase 2, inducible (Nos2) expression is necessary for the microbicidal activity of macrophages. However, NOS2 over-activation causes multiple inflammatory disorders, suggesting a tight gene regulation is necessary. Using cytosolic flagellin as a model for inflammasome-dependent NOS2 activation, we discovered a surprising new role for NLRC4/caspase-1 axis in regulating chromatin accessibility of the Nos2 promoter. We found that activation of two independent mechanisms is necessary for NOS2 expression by cytosolic flagellin: caspase-1 and NF-kappa B activation. NF-kappa B activation was necessary, but not sufficient, for NOS2 expression. Conversely, caspase-1 was necessary for NOS2 expression, but dispensable for NF-kappa B activation, indicating that this protease acts downstream NF-kappa B activation. We demonstrated that epigenetic regulation of Nos2 by caspase-1 involves cleavage of the chromatin regulator PARP1 (also known as ARTD1) and chromatin accessibility of the NF-kappa B binding sites located at the Nos2 promoter. Remarkably, caspase-1-mediated Nos2 transcription and NO production contribute to the resistance of macrophages to Salmonella typhimurium infection. Our results uncover the molecular mechanism behind the constricted regulation of Nos2 expression and open new therapeutic opportunities based on epigenetic activities of caspase-1 against infectious and inflammatory diseases.Kanton of ZurichUniversity Research Priority Program (URPP) in Translational Cancer Biology at the University of ZurichSwiss National Science FoundationCancer Research SocietyCanadian Cancer SocietyNSERCOntario Institute for Cancer Research (OICR)province of OntarioPrincess Margaret Cancer FoundationUniversity of Toronto McLaughlin CentreFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP - Brazil)Brazilian Research Council (CNPq-Brazil)CAPESINCTVUniv Fed Sao Paulo, Ctr Terapia Celular & Mol CTC Mol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Ciencias Biol, Sao Paulo, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo, BrazilUniv Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, CanadaUniv Sao Paulo, Inst Ciencias Biomed, Sao Paulo & Inst Invest Imunol, Inst Nacl Ciencia Tecnol INCT 3, Sao Paulo, BrazilInst Nacl Ciencia Tecnol INCT III, Inst Invest Imunol, Sao Paulo, BrazilUniv Zurich, Dept Mol Mech Dis, Zurich, SwitzerlandUniv Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, CanadaUniv Fed Sao Paulo, Ctr Terapia Celular & Mol CTC Mol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Ciencias Biol, Sao Paulo, BrazilSwiss National Science Foundation: 310030B_138667Cancer Research Society: CRS19092Cancer Research Society: CRS19091Canadian Cancer Society: CCSRI 703279Canadian Cancer Society CCSRI 703716NSERC: 489073University of Toronto McLaughlin Centre: MC-2015-02FAPESP: 2013/16010-5FAPESP: 2015/18003-1Web of Science-engNature Publishing GroupScientific ReportsEpigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavageinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleLondon7info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000393651700001.pdfapplication/pdf1648162${dspace.ui.url}/bitstream/11600/55124/1/WOS000393651700001.pdfe0faa9ac793573157b2a73818bf67955MD51open accessTEXTWOS000393651700001.pdf.txtWOS000393651700001.pdf.txtExtracted texttext/plain51664${dspace.ui.url}/bitstream/11600/55124/2/WOS000393651700001.pdf.txtdff19771438e156d4742f892e108fe7cMD52open accessTHUMBNAILWOS000393651700001.pdf.jpgWOS000393651700001.pdf.jpgIM Thumbnailimage/jpeg7377${dspace.ui.url}/bitstream/11600/55124/4/WOS000393651700001.pdf.jpg0e2e86b0460eeff77476b102925852e2MD54open access11600/551242022-08-01 04:47:45.92open accessoai:repositorio.unifesp.br:11600/55124Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652022-08-01T07:47:45Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage |
title |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage |
spellingShingle |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage Buzzo, Carina de Lima [UNIFESP] |
title_short |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage |
title_full |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage |
title_fullStr |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage |
title_full_unstemmed |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage |
title_sort |
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage |
author |
Buzzo, Carina de Lima [UNIFESP] |
author_facet |
Buzzo, Carina de Lima [UNIFESP] Medina, Tiago Branco, Laura M. [UNIFESP] Lage, Silvia L. [UNIFESP] de Souza Ferreira, Luis Carlos Amarante-Mendes, Gustavo P. Hottiger, Michael O. De Carvalho, Daniel D. Bortoluci, Karina R. [UNIFESP] |
author_role |
author |
author2 |
Medina, Tiago Branco, Laura M. [UNIFESP] Lage, Silvia L. [UNIFESP] de Souza Ferreira, Luis Carlos Amarante-Mendes, Gustavo P. Hottiger, Michael O. De Carvalho, Daniel D. Bortoluci, Karina R. [UNIFESP] |
author2_role |
author author author author author author author author |
dc.contributor.author.fl_str_mv |
Buzzo, Carina de Lima [UNIFESP] Medina, Tiago Branco, Laura M. [UNIFESP] Lage, Silvia L. [UNIFESP] de Souza Ferreira, Luis Carlos Amarante-Mendes, Gustavo P. Hottiger, Michael O. De Carvalho, Daniel D. Bortoluci, Karina R. [UNIFESP] |
description |
Nitric oxide synthase 2, inducible (Nos2) expression is necessary for the microbicidal activity of macrophages. However, NOS2 over-activation causes multiple inflammatory disorders, suggesting a tight gene regulation is necessary. Using cytosolic flagellin as a model for inflammasome-dependent NOS2 activation, we discovered a surprising new role for NLRC4/caspase-1 axis in regulating chromatin accessibility of the Nos2 promoter. We found that activation of two independent mechanisms is necessary for NOS2 expression by cytosolic flagellin: caspase-1 and NF-kappa B activation. NF-kappa B activation was necessary, but not sufficient, for NOS2 expression. Conversely, caspase-1 was necessary for NOS2 expression, but dispensable for NF-kappa B activation, indicating that this protease acts downstream NF-kappa B activation. We demonstrated that epigenetic regulation of Nos2 by caspase-1 involves cleavage of the chromatin regulator PARP1 (also known as ARTD1) and chromatin accessibility of the NF-kappa B binding sites located at the Nos2 promoter. Remarkably, caspase-1-mediated Nos2 transcription and NO production contribute to the resistance of macrophages to Salmonella typhimurium infection. Our results uncover the molecular mechanism behind the constricted regulation of Nos2 expression and open new therapeutic opportunities based on epigenetic activities of caspase-1 against infectious and inflammatory diseases. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017 |
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2020-07-17T14:03:00Z |
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2020-07-17T14:03:00Z |
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publishedVersion |
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Scientific Reports. London, v. 7, p. -, 2017. |
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https://repositorio.unifesp.br/handle/11600/55124 http://dx.doi.org/10.1038/srep41686 |
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2045-2322 |
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WOS000393651700001.pdf |
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10.1038/srep41686 |
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Scientific Reports. London, v. 7, p. -, 2017. 2045-2322 WOS000393651700001.pdf 10.1038/srep41686 WOS:000393651700001 |
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