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

UMMS Affiliation

Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology; Department of Cancer Biology; Department of Microbiology and Physiological Systems

Publication Date


Document Type



Immunology and Infectious Disease | Microbiology


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 IkappaB 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-1beta (IL-1beta). 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.

DOI of Published Version



Orning P, Weng D, Starheim K, Ratner D, Best Z, Lee B, Brooks A, Xia S, Wu H, Kelliher MA, Berger SB, Gough PJ, Bertin J, Proulx MM, Goguen JD, Kayagaki N, Fitzgerald KA, Lien E. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science. 2018 Nov 30;362(6418):1064-1069. doi: 10.1126/science.aau2818. Epub 2018 Oct 25. PMID: 30361383; PMCID: PMC6522129. Link to article on publisher's site

Journal/Book/Conference Title

Science (New York, N.Y.)


Full list of authors omitted for brevity. For full list see article.

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