Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death

Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe a...

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Published in:Science (American Association for the Advancement of Science) Vol. 362; no. 6418; p. 1064
Main Authors: Orning, Pontus, Weng, Dan, Starheim, Kristian, Ratner, Dmitry, Best, Zachary, Lee, Bettina, Brooks, Alexandria, Xia, Shiyu, Wu, Hao, Kelliher, Michelle A, Berger, Scott B, Gough, Peter J, Bertin, John, Proulx, Megan M, Goguen, Jon D, Kayagaki, Nobuhiko, Fitzgerald, Katherine A, Lien, Egil
Format: Journal Article
Language:English
Published: United States 30.11.2018
Subjects:
Animals
Apoptosis Regulatory Proteins - metabolism
Bacterial Proteins - metabolism
Caspase 8 - genetics
Caspase 8 - metabolism
Cell Death
Host-Pathogen Interactions
Humans
I-kappa B Kinase - metabolism
Inflammasomes - immunology
MAP Kinase Kinase Kinases - metabolism
Mice
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein
Plague - enzymology
Plague - immunology
Plague - pathology
Proteolysis
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary:Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe an additional pathway controlling GSDMD processing. The inhibition of TAK1 or IκB kinase (IKK) by the effector protein YopJ elicits RIPK1- and caspase-8-dependent cleavage of GSDMD, which subsequently results in cell death. GSDMD processing also contributes to the NLRP3 inflammasome-dependent release of interleukin-1β (IL-1β). Thus, caspase-8 acts as a regulator of GSDMD-driven cell death. Furthermore, this study establishes the importance of TAK1 and IKK activity in the control of GSDMD cleavage and cytotoxicity.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aau2818