CARD-like domains mediate anti-phage defense in bacterial gasdermin systems
Tanita Wein1, Alex G Johnson2,3, Adi Millman1
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Insights
CARD-like domains, ancient immune components, are found in bacterial anti-phage defenses, activating cell death similar to human inflammasomes. This ancient system highlights conserved innate immunity across life.
Area of Science:
- Microbiology
- Immunology
- Molecular Biology
Background:
- Caspase recruitment domains (CARDs) and pyrin domains are crucial for inflammasome activation and pyroptosis in eukaryotes.
- NLR proteins initiate inflammasome signaling by recruiting caspases, leading to gasdermin activation and pyroptotic cell death.
Approach:
- Investigated the presence and function of CARD-like domains in bacterial defense systems against bacteriophages.
- Characterized the role of bacterial CARDs in activating bacterial gasdermins and mediating cell death upon phage infection.
- Identified phage proteins that interact with bacterial CARD-gasdermin systems, including inhibitors.
Key Points:
- CARD-like domains are present in bacterial systems protecting against phage infection.
- Bacterial CARDs are essential for activating bacterial gasdermins, inducing cell death in response to phages.
- Multiple bacterial anti-phage systems utilize CARD-like domains to activate cell death effectors.
- Phage proteins can both trigger bacterial CARD systems and be inhibited by them, revealing complex immune evasion strategies.
Conclusions:
- CARD domains are ancient innate immune components conserved from bacteria to humans.
- CARD-dependent activation of gasdermins is a conserved mechanism across the tree of life for innate immunity.
Abstract:
Caspase recruitment domains (CARDs) and pyrin domains are important facilitators of inflammasome activity and pyroptosis. Upon pathogen recognition by NLR proteins, CARDs recruit and activate caspases, which, in turn, activate gasdermin pore forming proteins to and induce pyroptotic cell death. Here we show that CARD-like domains are present in defense systems that protect bacteria against phage. The bacterial CARD 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 defense systems utilize CARD-like domains to activate a variety of cell death effectors. We find that these systems are triggered by a conserved immune evasion protein that phages use to overcome the bacterial defense system RexAB, demonstrating that phage proteins inhibiting one defense system can activate another. We also detect a phage protein with a predicted CARD-like structure that can inhibit the CARD-containing bacterial gasdermin system. 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 conserved in organisms across the tree of life.
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