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

Autor(es)

Buzzo, Carina de Lima ; Medina, Tiago ; Branco, Laura M. ; Lage, Silvia L. ; de Souza Ferreira, Luis Carlos ; Amarante-Mendes, Gustavo P. ; Hottiger, Michael O. ; De Carvalho, Daniel D. ; Bortoluci, Karina R.

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 7, FEB 2 2017.
• Citações Web of Science: 9

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. (AU)

• Processo FAPESP: 15/18003-1 - Interação entre autofagia e receptores da imunidade inata para o controle da infecção pelo Trypanosoma cruzi
• Beneficiário: Karina Ramalho Bortoluci
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/16010-5 - Análise proteômica e funcional do papel diferencial de NLRC4, ASC e caspase-1 na ativação de macrófagos por flagelina citosólica
• Beneficiário: Karina Ramalho Bortoluci
• Modalidade de apoio: Auxílio à Pesquisa - Regular