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

ABSTRACT: 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 I?B kinase (IKK) by the Yersinia 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-1? (IL-1?). 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.

SUBMITTER: Orning P

PROVIDER: S-EPMC6522129 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Orning Pontus P Weng Dan D Starheim Kristian K Ratner Dmitry D Best Zachary Z Lee Bettina B Brooks Alexandria A Xia Shiyu S Wu Hao H Kelliher Michelle A MA Berger Scott B SB Gough Peter J PJ Bertin John J Proulx Megan M MM Goguen Jon D JD Kayagaki Nobuhiko N Fitzgerald Katherine A KA Lien Egil E

Science (New York, N.Y.) 20181025 6418

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 <i>Yersinia</i> effector protein YopJ elicits RIPK1- and caspase-8-dependent cleavage of GSDMD, whi ...[more]

PMID: 30361383

Dataset Information

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

Publications

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

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