Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense

Cell. 2020 Apr 30;181(3):674-687.e13. doi: 10.1016/j.cell.2020.03.040. Epub 2020 Apr 15.


Caspases regulate cell death, immune responses, and homeostasis. Caspase-6 is categorized as an executioner caspase but shows key differences from the other executioners. Overall, little is known about the functions of caspase-6 in biological processes apart from apoptosis. Here, we show that caspase-6 mediates innate immunity and inflammasome activation. Furthermore, we demonstrate that caspase-6 promotes the activation of programmed cell death pathways including pyroptosis, apoptosis, and necroptosis (PANoptosis) and plays an essential role in host defense against influenza A virus (IAV) infection. In addition, caspase-6 promoted the differentiation of alternatively activated macrophages (AAMs). Caspase-6 facilitated the RIP homotypic interaction motif (RHIM)-dependent binding of RIPK3 to ZBP1 via its interaction with RIPK3. Altogether, our findings reveal a vital role for caspase-6 in facilitating ZBP1-mediated inflammasome activation, cell death, and host defense during IAV infection, opening additional avenues for treatment of infectious and autoinflammatory diseases and cancer.

Keywords: AAMs; NLRP3; PANoptosis; RIPK1; RIPK3; ZBP1; apoptosis; caspase-1; caspase-6; caspase-8; inflammasome; influenza A virus; necroptosis; pyroptosis.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Caspase 6 / immunology*
  • Caspase 6 / metabolism*
  • Cell Death / immunology
  • Immunity, Innate
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Inflammasomes / physiology
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Necroptosis / immunology
  • Protein Binding
  • Pyroptosis / immunology
  • RNA-Binding Proteins / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA-Binding Proteins
  • Zbp1 protein, mouse
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Casp6 protein, mouse
  • Caspase 6