Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death
Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology; Department of Cancer Biology; Department of Microbiology and Physiological Systems
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
Science (New York, N.Y.)
Orning MA, Wang D, Starheim KK, Ratner D, Best Z, Lee B, Brooks A, Xia S, Wu H, Kelliher MA, Berger SB, Proulx MK, Goguen JD, Fitzgerald KA, Lien E. (2018). Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Infectious Diseases and Immunology Publications. https://doi.org/10.1126/science.aau2818. Retrieved from https://escholarship.umassmed.edu/infdis_pp/419