Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages.
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.
Suzuki
Toshihiko
T
Division of Bacterial Pathogenesis, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan. t-suzuki@med.u-ryukyu.ac.jp
Franchi
Luigi
L
Toma
Claudia
C
Ashida
Hiroshi
H
Ogawa
Michinaga
M
Yoshikawa
Yuko
Y
Mimuro
Hitomi
H
Inohara
Naohiro
N
Sasakawa
Chihiro
C
Nuñez
Gabriel
G
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001854:Bone Marrow Cells; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D012763:Shigella flexneri / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C498534:Pycard protein, mouse; C025946:3-methyladenine; D020170:Caspase 1; D000225:Adenine
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