Differential Regulation of caspase-1 Activation, Pyroptosis, and Autophagy via Ipaf and ASC in Shigella-infected Macrophages

PLoS Pathog. 2007 Aug 10;3(8):e111. doi: 10.1371/journal.ppat.0030111.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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