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

Pontus Ørning | Zendy; Dan Weng | Zendy; Kristian K. Starheim | Zendy; Dmitry Ratner | Zendy; Zachary Best | Zendy; Bettina Lee | Zendy; Alexandria Brooks | Zendy; Shiyu Xia | Zendy; Hao Wu | Zendy; Michelle A. Kelliher | Zendy; Scott B. Berger | Zendy; Peter J. Gough | Zendy; John Bertin | Zendy; Megan K. Proulx | Zendy; Jon D. Goguen | Zendy; Nobuhiko Kayagaki | Zendy; Katherine A. Fitzgerald | Zendy; Egil Lien | Zendy

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

Author(s) -

Pontus Ørning,

Dan Weng,

Kristian K. Starheim,

Dmitry Ratner,

Zachary Best,

Bettina Lee,

Alexandria Brooks,

Shiyu Xia,

Hao Wu,

Michelle A. Kelliher,

Scott B. Berger,

Peter J. Gough,

John Bertin,

Megan K. Proulx,

Jon D. Goguen,

Nobuhiko Kayagaki,

Katherine A. Fitzgerald,

Egil Lien

Publication year - 2018

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aau2818

Subject(s) - pyroptosis , inflammasome , caspase 1 , effector , microbiology and biotechnology , programmed cell death , cleavage (geology) , pathogen , caspase , receptor , inflammation , biology , chemistry , apoptosis , immunology , biochemistry , paleontology , fracture (geology)

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 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-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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