CARD domains mediate anti-phage defence in bacterial gasdermin systems
Tanita Wein1, Adi Millman1, Katharina Lange1
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Insights
Bacterial defense systems utilize caspase recruitment domains (CARDs) to activate gasdermins and induce cell death against phages. This ancient innate immunity mechanism is conserved across life, from bacteria to humans.
Area of Science:
- Innate immunity
- Microbial defense systems
- Molecular mechanisms of cell death
Background:
- Caspase recruitment domains (CARDs) and pyrin domains facilitate inflammasome activity and pyroptosis in eukaryotes.
- NLR proteins initiate inflammatory responses by recruiting and activating caspases, leading to pyroptosis.
Purpose of the Study:
- To investigate the role of CARD domains in bacterial defense systems against phages.
- To explore the conserved nature of CARD domains in innate immunity across different life forms.
Main Methods:
- Analysis of bacterial defense systems involving CARD domains.
- Investigating CARD domain-mediated protein-protein interactions.
- Characterizing the activation of bacterial gasdermins by CARD domains.
Main Results:
- CARD domains are integral components of bacterial anti-phage defense systems.
- Bacterial CARD domains mediate protease-dependent activation of gasdermins, inducing cell death upon phage recognition.
- Multiple anti-phage systems employ CARD domains to activate cell death effectors, triggered by phage immune evasion proteins.
Conclusions:
- CARD domains are ancient, conserved components of innate immune systems in both bacteria and humans.
- CARD-dependent activation of gasdermins is a fundamental mechanism of cell death conserved across the tree of life.
Abstract:
Caspase recruitment domains (CARDs) and pyrin domains are important facilitators of inflammasome activity and pyroptosis1. Following pathogen recognition by nucleotide binding-domain, leucine-rich, repeat-containing (NLR) proteins, CARDs recruit and activate caspases, which, in turn, activate gasdermin pore-forming proteins to induce pyroptotic cell death2. Here we show that CARD domains are present in defence systems that protect bacteria against phage. The bacterial CARD domain is essential for protease-mediated activation of certain bacterial gasdermins, which promote cell death once phage infection is recognized. We further show that multiple anti-phage defence systems use CARD domains to activate a variety of cell death effectors, and that CARD domains mediate protein-protein interactions in these systems. We find that these systems are triggered by a conserved immune-evasion protein used by phages to overcome the bacterial defence system RexAB3, demonstrating that phage proteins inhibiting one defence system can activate another. Our results suggest that CARD domains represent an ancient component of innate immune systems conserved from bacteria to humans, and that CARD-dependent activation of gasdermins is shared in organisms across the tree of life.
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