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Title :Differential Regulation of Caspase-1 Activation, Pyroptosis, and Autophagy via Ipaf and ASC in Shigella-Infected Macrophages
Authors :Suzuki, Toshihiko
Franchi, Luigi
Toma, Claudia
Ashida, Hiroshi
Ogawa, Michinaga
Yoshikawa, Yuko
Mimuro, Hitomi
Inohara, Naohiro
Sasakawa, Chihiro
Nunez, Gabriel
Issue Date :10-Aug-2007
Abstract :Shigella infection, the cause of bacillary dysentery, induces caspase-1 activation and cell death in macrophages, but the precise mechanisms of this activation remain poorly understood. We demonstrate here that caspase-1 activation and IL-1β processing induced by Shigella are mediated through Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, and the adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). We also show that Ipaf was critical for pyroptosis, a specialized form of caspase-1-dependent cell death induced in macrophages by bacterial infection, whereas ASC was dispensable. Unlike that observed in Salmonella and Legionella, caspase-1 activation induced by Shigella infection was independent of flagellin. Notably, infection of macrophages with Shigella induced autophagy, which was dramatically increased by the absence of caspase-1 or Ipaf, but not ASC. Autophagy induced by Shigella required an intact bacterial type III secretion system but not VirG protein, a bacterial factor required for autophagy in epithelial-infected cells. Treatment of macrophages with 3-methyladenine, an inhibitor of autophagy, enhanced pyroptosis induced by Shigella infection, suggesting that autophagy protects infected macrophages from pyroptosis. Thus, Ipaf plays a critical role in caspase-1 activation induced by Shigella independently of flagellin. Furthermore, the absence of Ipaf or caspase-1, but not ASC, regulates pyroptosis and the induction of autophagy in Shigella-infected macrophages, providing a novel function for NLR proteins in bacterial–host interactions.
URL :https://doi.org/10.1371/journal.ppat.0030111
Type Local :雑誌掲載論文
ISSN :1553-7366
1553-7374
Publisher :Public Library of Science
URI :http://hdl.handle.net/20.500.12000/47240
Citation :PLoS Pathogens Vol.3 no.8 p.1082 -1091
Appears in Collections:Peer-reviewed Journal Articles (Faculty of Medicine)

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