Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage
Buzzo, Carina de Lima [UNIFESP]
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]
Is part ofScientific Reports
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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.
CitationScientific Reports. London, v. 7, p. -, 2017.
SponsorshipKanton 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)
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