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Imaging Ca2+ Responses During Shigella Infection of Epithelial Cells
Published on: May 24, 2018
BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella
Maria Andree1, Jens M Seeger1, Stephan Schüll1
1Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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.
Insights
Shigella flexneri evades immune responses by triggering SMAC release, which inhibits XIAP. This pathogen subverts cell death pathways via calpain-dependent BID cleavage to promote bacterial colonization.
Area of Science:
- Cellular and Molecular Immunology
- Pathogen-Host Interactions
- Apoptosis and Cell Death Pathways
Background:
- X-linked inhibitor of apoptosis protein (XIAP) is a key caspase inhibitor, primarily known for its anti-apoptotic role in cancer.
- SMAC (second mitochondria-derived activator of caspases) antagonizes XIAP during apoptosis by being released from mitochondria.
- Emerging evidence suggests XIAP's involvement in immune signaling pathways.
Purpose of the Study:
- To investigate the role of XIAP in the immune response against the enteroinvasive bacterium Shigella flexneri.
- To elucidate the mechanism by which Shigella evades XIAP-mediated immunity.
Main Methods:
- In vitro and in vivo studies using Shigella flexneri infection models.
- Analysis of XIAP, SMAC, BID, and calpain interactions during infection.
- Assessment of bacterial colonization and immune response modulation.
Main Results:
- Shigella flexneri induces the BID-dependent release of SMAC from mitochondria, antagonizing XIAP's inflammatory function.
- Unlike apoptotic stimuli, Shigella employs a calpain-dependent cleavage of BID to trigger SMAC release, thereby avoiding host cell apoptosis.
- This evasion strategy allows Shigella to subvert cellular death machinery for successful bacterial colonization.
Conclusions:
- XIAP is a critical mediator of the immune response against Shigella flexneri.
- Shigella utilizes a novel mechanism involving calpain-mediated BID cleavage and SMAC release to counteract XIAP-driven immunity.
- Pathogens can subvert host cell death pathways to facilitate infection and colonization.
