Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages

• Published in: PLoS pathogens 2007-08, Vol.3 (8), p.e111-e111
• Main Authors: Suzuki, Toshihiko, Franchi, Luigi, Toma, Claudia, Ashida, Hiroshi, Ogawa, Michinaga, Yoshikawa, Yuko, Mimuro, Hitomi, Inohara, Naohiro, Sasakawa, Chihiro, Nuñez, Gabriel
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; Autophagy - physiology; Bacterial diseases; Bacterial infections; Bone Marrow Cells; Calcium-Binding Proteins - metabolism; CARD Signaling Adaptor Proteins; Caspase 1 - biosynthesis; Caspase 1 - genetics; Cell Biology; Cells, Cultured; Cytoskeletal Proteins - metabolism; Dysentery; Enzyme activation; Enzymes; Eubacteria; Gene Expression Regulation, Enzymologic; Gene Silencing; Immunology; Infectious Diseases; Influence; Interleukin-1beta - metabolism; Macrophages; Macrophages - enzymology; Macrophages - microbiology; Macrophages - pathology; Mammals; Methods; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Mus (Mouse); Necrosis; Observations; Proteins; Regulation; Shigella flexneri - physiology; Shigellosis; Waterborne diseases
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.0030111

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-1beta 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.