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Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex.


ABSTRACT: 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? 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? 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? processing during Salmonella infection.

SUBMITTER: Man SM 

PROVIDER: S-EPMC4034195 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex.

Man Si Ming SM   Hopkins Lee J LJ   Nugent Eileen E   Cox Susan S   Glück Ivo M IM   Tourlomousis Panagiotis P   Wright John A JA   Cicuta Pietro P   Monie Tom P TP   Bryant Clare E CE  

Proceedings of the National Academy of Sciences of the United States of America 20140506 20


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 Salmonell  ...[more]

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