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

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-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.

• Authors: Toshihiko Suzuki, Luigi Franchi, Claudia Toma, Hiroshi Ashida, Michinaga Ogawa, Yuko Yoshikawa, Hitomi Mimuro, Naohiro Inohara, Chihiro Sasakawa, Gabriel Nuñez
• Journal: PLoS pathogens (PLoS Pathog) Vol. 3 Issue 8 Pg. e111 (Aug 10 2007) ISSN: 1553-7374 [Electronic] United States
• PMID: 17696608 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Calcium-Binding Proteins
• Cytoskeletal Proteins
• Interleukin-1beta
• Ipaf protein, mouse
• Pycard protein, mouse
• 3-methyladenine
• Caspase 1
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects, physiology)
• Bone Marrow Cells
• CARD Signaling Adaptor Proteins
• Calcium-Binding Proteins (metabolism)
• Caspase 1 (biosynthesis, genetics)
• Cells, Cultured
• Cytoskeletal Proteins (metabolism)
• Gene Expression Regulation, Enzymologic
• Gene Silencing
• Interleukin-1beta (metabolism)
• Macrophages (enzymology, microbiology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Necrosis
• Shigella flexneri (physiology)