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Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-κB target genes.
Caspase 1 is part of the inflammasome, which is assembled upon pathogen recognition, while caspases 3 and/or 7 are mediators of apoptotic and nonapoptotic functions. PARP1 cleavage is a hallmark of apoptosis yet not essential, suggesting it has another physiological role. Here we show that after LPS stimulation, caspase 7 is activated by caspase 1, translocates to the nucleus, and cleaves PARP1 at the promoters of a subset of NF-κB target genes negatively regulated by PARP1. Mutating the PARP1 cleavage site D214 renders PARP1 uncleavable and inhibits PARP1 release from chromatin and chromatin decondensation, thereby restraining the expression of cleavage-dependent NF-κB target genes. These findings propose an apoptosis-independent regulatory role for caspase 7-mediated PARP1 cleavage in proinflammatory gene expression and provide insight into inflammasome signaling.
Animals, Carrier Proteins/genetics, Carrier Proteins/metabolism, Caspase 7/physiology, Chromatin/metabolism, Gene Expression Regulation, Humans, Inflammation/genetics, Mice, Mutation, NF-kappa B/metabolism, Poly(ADP-ribose) Polymerases/chemistry, Poly(ADP-ribose) Polymerases/genetics, Signal Transduction
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