期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 21, 页码 7765-7770出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1400075111
关键词
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资金
- National Institutes of Health [AI46454, AI083713]
- New England Regional Center for Excellence (NERCE) Post-Doctoral Fellowship Award [U54 AI057159]
Enterohemorrhagic Escherichia coli (EHEC) is an extracellular pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. The proinflammatory cytokine, interleukin-1 beta, has been linked to hemolytic uremic syndrome. Here we identify the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome as an essential mediator of EHEC-induced IL-1 beta. Whereas EHEC-specific virulence factors were dispensable for NLRP3 activation, bacterial nucleic acids such as RNA: DNA hybrids and RNA gained cytosolic access and mediated inflammasome-dependent responses. Consistent with a direct role for RNA: DNA hybrids in inflammasome activation, delivery of synthetic EHEC RNA: DNA hybrids into the cytosol triggered NLRP3-dependent responses, and introduction of RNase H, which degrades such hybrids, into infected cells specifically inhibited inflammasome activation. Notably, an E. coli rnhA mutant, which is incapable of producing RNase H and thus harbors increased levels of RNA:DNA hybrid, induced elevated levels of NLRP3-dependent caspase-1 activation and IL-1 beta maturation. Collectively, these findings identify RNA: DNA hybrids of bacterial origin as a unique microbial trigger of the NLRP3 inflammasome.
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