Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage

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dc.citation.volume7
dc.contributor.authorBuzzo, Carina de Lima [UNIFESP]
dc.contributor.authorMedina, Tiago
dc.contributor.authorBranco, Laura M. [UNIFESP]
dc.contributor.authorLage, Silvia L. [UNIFESP]
dc.contributor.authorde Souza Ferreira, Luis Carlos
dc.contributor.authorAmarante-Mendes, Gustavo P.
dc.contributor.authorHottiger, Michael O.
dc.contributor.authorDe Carvalho, Daniel D.
dc.contributor.authorBortoluci, Karina R. [UNIFESP]
dc.coverageLondon
dc.date.accessioned2020-07-17T14:03:00Z
dc.date.available2020-07-17T14:03:00Z
dc.date.issued2017
dc.description.abstractNitric 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.en
dc.description.affiliationUniv Fed Sao Paulo, Ctr Terapia Celular & Mol CTC Mol, Sao Paulo, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Dept Ciencias Biol, Sao Paulo, Brazil
dc.description.affiliationUniv Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo, Brazil
dc.description.affiliationUniv Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada
dc.description.affiliationUniv Sao Paulo, Inst Ciencias Biomed, Sao Paulo & Inst Invest Imunol, Inst Nacl Ciencia Tecnol INCT 3, Sao Paulo, Brazil
dc.description.affiliationInst Nacl Ciencia Tecnol INCT III, Inst Invest Imunol, Sao Paulo, Brazil
dc.description.affiliationUniv Zurich, Dept Mol Mech Dis, Zurich, Switzerland
dc.description.affiliationUniv Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada
dc.description.affiliationUnifespUniv Fed Sao Paulo, Ctr Terapia Celular & Mol CTC Mol, Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Ciencias Biol, Sao Paulo, Brazil
dc.description.provenanceMade available in DSpace on 2020-07-17T14:03:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2017. Added 1 bitstream(s) on 2020-07-17T14:33:33Z : No. of bitstreams: 1 WOS000393651700001.pdf: 1648162 bytes, checksum: e0faa9ac793573157b2a73818bf67955 (MD5)en
dc.description.sourceWeb of Science
dc.description.sponsorshipKanton of Zurich
dc.description.sponsorshipUniversity Research Priority Program (URPP) in Translational Cancer Biology at the University of Zurich
dc.description.sponsorshipSwiss National Science Foundation
dc.description.sponsorshipCancer Research Society
dc.description.sponsorshipCanadian Cancer Society
dc.description.sponsorshipNSERC
dc.description.sponsorshipOntario Institute for Cancer Research (OICR)
dc.description.sponsorshipprovince of Ontario
dc.description.sponsorshipPrincess Margaret Cancer Foundation
dc.description.sponsorshipUniversity of Toronto McLaughlin Centre
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP - Brazil)
dc.description.sponsorshipBrazilian Research Council (CNPq-Brazil)
dc.description.sponsorshipCAPES
dc.description.sponsorshipINCTV
dc.description.sponsorshipIDSwiss National Science Foundation: 310030B_138667
dc.description.sponsorshipIDCancer Research Society: CRS19092
dc.description.sponsorshipIDCancer Research Society: CRS19091
dc.description.sponsorshipIDCanadian Cancer Society: CCSRI 703279
dc.description.sponsorshipIDCanadian Cancer Society CCSRI 703716
dc.description.sponsorshipIDNSERC: 489073
dc.description.sponsorshipIDUniversity of Toronto McLaughlin Centre: MC-2015-02
dc.description.sponsorshipIDFAPESP: 2013/16010-5
dc.description.sponsorshipIDFAPESP: 2015/18003-1
dc.format.extent-
dc.identifierhttp://dx.doi.org/10.1038/srep41686
dc.identifier.citationScientific Reports. London, v. 7, p. -, 2017.
dc.identifier.doi10.1038/srep41686
dc.identifier.fileWOS000393651700001.pdf
dc.identifier.issn2045-2322
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/55124
dc.identifier.wosWOS:000393651700001
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofScientific Reports
dc.rightsAcesso aberto
dc.titleEpigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavageen
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