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

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

Author Buzzo, Carina de Lima Autor UNIFESP Google Scholar
Medina, Tiago Google Scholar
Branco, Laura M. Autor UNIFESP Google Scholar
Lage, Silvia L. Autor UNIFESP Google Scholar
de Souza Ferreira, Luis Carlos Google Scholar
Amarante-Mendes, Gustavo P. Google Scholar
Hottiger, Michael O. Google Scholar
De Carvalho, Daniel D. Google Scholar
Bortoluci, Karina R. Autor UNIFESP Google Scholar
Abstract 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.
xmlui.dri2xhtml.METS-1.0.item-coverage London
Language English
Sponsor Kanton of Zurich
University Research Priority Program (URPP) in Translational Cancer Biology at the University of Zurich
Swiss National Science Foundation
Cancer Research Society
Canadian Cancer Society
Ontario Institute for Cancer Research (OICR)
province of Ontario
Princess Margaret Cancer Foundation
University of Toronto McLaughlin Centre
Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP - Brazil)
Brazilian Research Council (CNPq-Brazil)
Grant number Swiss National Science Foundation: 310030B_138667
Cancer Research Society: CRS19092
Cancer Research Society: CRS19091
Canadian Cancer Society: CCSRI 703279
Canadian Cancer Society CCSRI 703716
NSERC: 489073
University of Toronto McLaughlin Centre: MC-2015-02
FAPESP: 2013/16010-5
FAPESP: 2015/18003-1
Date 2017
Published in Scientific Reports. London, v. 7, p. -, 2017.
ISSN 2045-2322 (Sherpa/Romeo, impact factor)
Publisher Nature Publishing Group
Extent -
Origin http://dx.doi.org/10.1038/srep41686
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000393651700001
URI https://repositorio.unifesp.br/handle/11600/55124

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