Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway

The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known t...

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Bibliographic Details
Published in:	Cell Vol. 184; no. 17; p. 4495
Main Authors:	Evavold, Charles L, Hafner-Bratkovič, Iva, Devant, Pascal, D'Andrea, Jasmin M, Ngwa, Elsy M, Boršić, Elvira, Doench, John G, LaFleur, Martin W, Sharpe, Arlene H, Thiagarajah, Jay R, Kagan, Jonathan C
Format:	Journal Article
Language:	English
Published:	United States 19.08.2021
Subjects:	Adaptor Proteins, Signal Transducing - metabolism Amino Acids - metabolism Animals Cell Adhesion Molecules, Neuronal - metabolism Cell Line Genetic Testing Humans Inflammasomes - metabolism Intracellular Signaling Peptides and Proteins - chemistry Intracellular Signaling Peptides and Proteins - metabolism Macrophages - metabolism Mechanistic Target of Rapamycin Complex 1 - metabolism Mechanistic Target of Rapamycin Complex 2 - metabolism Mice, Inbred C57BL Mitochondria - metabolism Monomeric GTP-Binding Proteins - metabolism Nerve Growth Factors - metabolism NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Phosphate-Binding Proteins - chemistry Phosphate-Binding Proteins - metabolism Protein Domains Protein Multimerization Pyroptosis Reactive Oxygen Species - metabolism RNA, Guide, CRISPR-Cas Systems Signal Transduction TOR Serine-Threonine Kinases - metabolism pyroptosis ragulator macrophages gasdermin D innate immunity inflammasomes inflammation reactive oxygen species mtorc1
ISSN:	1097-4172, 1097-4172
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Summary:	The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2021.06.028