BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella

EMBO J. 2014 Oct 1;33(19):2171-87. doi: 10.15252/embj.201387244. Epub 2014 Jul 23.

Abstract

The X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor, best known for its anti-apoptotic function in cancer. During apoptosis, XIAP is antagonized by SMAC, which is released from the mitochondria upon caspase-mediated activation of BID. Recent studies suggest that XIAP is involved in immune signaling. Here, we explore XIAP as an important mediator of an immune response against the enteroinvasive bacterium Shigella flexneri, both in vitro and in vivo. Our data demonstrate for the first time that Shigella evades the XIAP-mediated immune response by inducing the BID-dependent release of SMAC from the mitochondria. Unlike apoptotic stimuli, Shigella activates the calpain-dependent cleavage of BID to trigger the release of SMAC, which antagonizes the inflammatory action of XIAP without inducing apoptosis. Our results demonstrate how the cellular death machinery can be subverted by an invasive pathogen to ensure bacterial colonization.

Keywords: SMAC; Shigella; XIAP; inflammation; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein / physiology*
  • Blotting, Western
  • Carrier Proteins / metabolism*
  • Caspases / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Dysentery, Bacillary / immunology*
  • Dysentery, Bacillary / microbiology
  • Dysentery, Bacillary / pathology
  • Female
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Immunoenzyme Techniques
  • Integrases / metabolism
  • Male
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / immunology*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Proteins / immunology
  • Mitochondrial Proteins / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Shigella / immunology*
  • Shigella / pathogenicity
  • Signal Transduction
  • Spectrometry, Mass, Electrospray Ionization
  • Tandem Mass Spectrometry
  • X-Linked Inhibitor of Apoptosis Protein / physiology*

Substances

  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Bid protein, mouse
  • Carrier Proteins
  • Diablo protein, mouse
  • Mitochondrial Proteins
  • RNA, Messenger
  • X-Linked Inhibitor of Apoptosis Protein
  • Cre recombinase
  • Integrases
  • Caspases