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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Vydané v:Science (American Association for the Advancement of Science) Ročník 362; číslo 6418; s. 1064
Hlavní autori: 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
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 30.11.2018
Predmet:
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
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Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1095-9203
1095-9203
DOI:10.1126/science.aau2818