CARD domains mediate anti-phage defence in bacterial gasdermin systems

Tanita Wein; Adi Millman; Katharina Lange; Erez Yirmiya; Romi Hadary; Jeremy Garb; Sarah Melamed; Gil Amitai; Orly Dym; Felix Steinruecke; Aidan B. Hill; Philip J. Kranzusch; Rotem Sorek

doi:10.1038/s41586-024-08498-3

CARD domains mediate anti-phage defence in bacterial gasdermin systems

Tanita Wein, Adi Millman, Katharina Lange, Erez Yirmiya, Romi Hadary, Jeremy Garb, Sarah Melamed, Gil Amitai, Orly Dym, Felix Steinruecke, Aidan B. Hill, Philip J. Kranzusch^*, Rotem Sorek^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Pages (from-to)	727-734
Number of pages	8
Journal	Nature
Volume	639
Issue number	8055
Early online date	29 Jan 2025
DOIs	https://doi.org/10.1038/s41586-024-08498-3
Publication status	Published - 20 Mar 2025

Funding

We thank the Sorek and Kranzusch laboratory members for comments on the manuscript and fruitful discussions. R.S. was supported, in part, by the European Research Council (grant no. ERC-AdG GA 101018520), Israel Science Foundation (MAPATS grant no. 2720/22), Deutsche Forschungsgemeinschaft (SPP 2330, grant no. 464312965), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine and the Knell Family Center for Microbiology. P.J.K. was supported, in part, by the Pew Biomedical Scholars programme, The G. Harold and Leila Y. Mathers Charitable Foundation, the Parker Institute for Cancer Immunotherapy and the National Institutes of Health (no. 1DP2GM146250). T.W. was supported by a Minerva Foundation postdoctoral fellowship and by a European Molecular Biology Organization postdoctoral fellowship (no. ALTF 946-2020). A.M. was supported by a fellowship from the Ariane de Rothschild Women Doctoral Program and, in part, by the Israeli Council for Higher Education by the Weizmann Data Science Research Center. E.Y. was supported, in part, by the Israeli Council for Higher Education by the Weizmann Data Science Research Center. X-ray data were collected at Northeastern Collaborative Access Team beamlines 24-ID-C and 24-ID-E (P30 GM124165), including the use of a Pilatus detector (S10RR029205), an Eiger detector (S10OD021527) and the Argonne National Laboratory Advanced Photon Source (DE-AC02-06CH11357).

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title = "CARD domains mediate anti-phage defence in bacterial gasdermin systems",

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.",

author = "Tanita Wein and Adi Millman and Katharina Lange and Erez Yirmiya and Romi Hadary and Jeremy Garb and Sarah Melamed and Gil Amitai and Orly Dym and Felix Steinruecke and Hill, \{Aidan B.\} and Kranzusch, \{Philip J.\} and Rotem Sorek",

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AU - Wein, Tanita

AU - Millman, Adi

AU - Lange, Katharina

AU - Yirmiya, Erez

AU - Hadary, Romi

AU - Garb, Jeremy

AU - Melamed, Sarah

AU - Amitai, Gil

AU - Dym, Orly

AU - Steinruecke, Felix

AU - Hill, Aidan B.

AU - Kranzusch, Philip J.

AU - Sorek, Rotem

PY - 2025/3/20

Y1 - 2025/3/20

N2 - 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.

AB - 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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CARD domains mediate anti-phage defence in bacterial gasdermin systems

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