Regulating the unregulated: what host factors are required for GSDMD pore formation?
| Autor: | Charles Lee Evavold, Iva Hafner-Bratkovic, Pascal Devant, Jonathan C. Kagan |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 206:111.06-111.06 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Cleavage of gasdermin D (GSDMD) by inflammatory caspases results in pore formation at the plasma membrane. GSDMD pores are recognized to mediate pyroptotic lysis of the cell or direct translocation of IL-1 family cytokines from the cytosol into the extracellular space. While several regulators of GSDMD cleavage have been identified, positive regulators of pore formation that act after cleavage have occurred are unknown. To identify proteins that promote GSDMD pore formation at the plasma membrane after GSDMD cleavage, we utilized a genome-wide CRISPR/Cas9 screening platform in macrophages. This screen uncovered a novel link between host metabolism and cell death at the level of GSDMD pore oligomerization. Several hits in this screen belong to the Ragulator-Rag complex that serves to activate mTORC1. Our data suggests that this Ragulator-Rag-mTORC1 axis promotes pyroptosis through enforcing functional GSDMD pore formation. |
| Databáze: | OpenAIRE |
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