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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Bacterial Proteins / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Death
  • Host-Pathogen Interactions*
  • Humans
  • I-kappa B Kinase / metabolism*
  • Inflammasomes / immunology
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phosphate-Binding Proteins
  • Plague / enzymology
  • Plague / immunology*
  • Plague / pathology
  • Proteolysis


  • Apoptosis Regulatory Proteins
  • Bacterial Proteins
  • Gsdmd protein, mouse
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phosphate-Binding Proteins
  • YopP protein, Yersinia
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Caspase 8