Pore formation at the lytic synapse triggers the canonical pyroptotic cell death pathway

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Pore formation at the lytic synapse triggers the canonical pyroptotic cell death pathway

Authors

McKenzie, B.; Puissegur, M.-P.; Demeersseman, L.; Rodriguez, F.; Cini, E.; Mueller, S.; Valitutti, S.

Abstract

Antigen-specific cytotoxic T lymphocytes (CTLs) kill targets through rapid release of perforin/granzymes into the lytic synapse. Lethal hit delivery activates programmed cell death in the target, which is classically considered apoptotic, caspase-mediated, and granzyme-dependent. Herein, we propose an unprecedented role for perforin in triggering target cell pyroptosis, complementing its well-documented role as a conduit for granzymes. Utilizing imaging and molecular approaches, we demonstrate that target perforation upon CTL attack elicits swift K+ efflux, triggering the canonical inflammatory pyroptotic signaling cascade defined by activation of the NLRP3 inflammasome, caspase-1, and the pore-forming pyroptotic executioner, gasdermin D (GSDMD); this is followed by pyroptotic body formation, plasma membrane rupture, and release of intracellular contents. Disruption of perforin inhibited this pathway, while recombinant perforin activated caspase-1-dependent pyroptosis. These results reveal that perforin retains the pro-pyroptotic activity of ancestral pore-forming toxins, and highlight a previously unappreciated role for the canonical caspase-1/GSDMD pyroptotic pathway in adaptive immunity.

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