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

被引：712

作者：

Orning, Pontus ^{[1
,2
]}

Weng, Dan ^{[1
,3
]}

Starheim, Kristian ^{[1
,2
]}

Ratner, Dmitry ^{[1
]}

Best, Zachary ^{[1
]}

Lee, Bettina ^{[4
]}

Brooks, Alexandria ^{[1
]}

Xia, Shiyu ^{[5
,6
]}

Wu, Hao ^{[5
,6
]}

Kelliher, Michelle A. ^{[7
]}

Berger, Scott B. ^{[8
]}

Gough, Peter J. ^{[8
]}

Bertin, John ^{[8
]}

Proulx, Megan M. ^{[9
]}

Goguen, Jon D. ^{[9
]}

Kayagaki, Nobuhiko ^{[4
]}

Fitzgerald, Katherine A. ^{[2
]}

Lien, Egil ^{[1
,2
]}

机构：

[1] Univ Massachusetts, Div Infect Dis & Immunol, Dept Med, Program Innate Immun,Med Sch, Worcester, MA 01605 USA

[2] Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Ctr Mol Inflammat Res, N-7491 Trondheim, Norway

[3] Nanjing Univ Sci & Technol, Ctr Mol Metab, Nanjing 210094, Jiangsu, Peoples R China

[4] Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA

[5] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[6] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[7] Univ Massachusetts, Dept Canc Biol, Med Sch, Worcester, MA 01605 USA

[8] GlaxoSmithKline, Pattern Recognit Receptor Discovery Performance U, Immunoinflammat Therapeut Area, Collegeville, PA 19426 USA

[9] Univ Massachusetts, Dept Microbiol & Physiol, Med Sch, Worcester, MA 01655 USA

来源：

SCIENCE | 2018年 / 362卷 / 6418期

基金：

美国国家卫生研究院;

关键词：

NF-KAPPA-B; YERSINIA-PESTIS; ACTIVATION; CASPASE-1; PYROPTOSIS; NECROSIS; GSDMD; TRIF; PHOSPHORYLATION; COLONIZATION;

D O I：

10.1126/science.aau2818

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 kappa 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 beta (IL-1 beta). 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.

引用

页码：1064 / +

页数：32

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