期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 20, 页码 7403-7408出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1402911111
关键词
innate immunity; bacteria; caspase-1; caspase-8; ASC
资金
- Wellcome Trust [WT085090MA]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/H003916/1, BB/K006436/1]
- BBSRC [BB/H021930/1]
- Cambridge International Scholarship
- BBSRC [BB/K01563X/1, BB/K006436/1, BB/H003916/1, BB/H021930/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H003916/1, BB/K006436/1, BB/H021930/1, BB/K01563X/1] Funding Source: researchfish
Pathogen recognition by nucleotide-binding oligomerization domain-like receptor (NLR) results in the formation of a macromolecular protein complex (inflammasome) that drives protective inflammatory responses in the host. It is thought that the number of inflammasome complexes forming in a cell is determined by the number of NLRs being activated, with each NLR initiating its own inflammasome assembly independent of one another; however, we show here that the important foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) simultaneously activates at least two NLRs, whereas only a single inflammasome complex is formed in a macrophage. Both nucleotide-binding domain and leucine-rich repeat caspase recruitment domain 4 and nucleotide-binding domain and leucine-rich repeat pyrin domain 3 are simultaneously present in the same inflammasome, where both NLRs are required to drive IL-1 beta processing within the Salmonella-infected cell and to regulate the bacterial burden in mice. Superresolution imaging of Salmonella-infected macrophages revealed a macromolecular complex with an outer ring of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain and an inner ring of NLRs, with active caspase effectors containing the pro-IL-1 beta substrate localized internal to the ring structure. Our data reveal the spatial localization of different components of the inflammasome and how different members of the NLR family cooperate to drive robust IL-1 beta processing during Salmonella infection.
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