RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling

Proc Natl Acad Sci U S A. 2021 Jul 13;118(28):e2101189118. doi: 10.1073/pnas.2101189118.


Injection of effector proteins to block host innate immune signaling is a common strategy used by many pathogenic organisms to establish an infection. For example, pathogenic Yersinia species inject the acetyltransferase YopJ into target cells to inhibit NF-κB and MAPK signaling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death-inducing platform that confers antibacterial defense. While recent studies revealed that caspase-8 cleaves the pore-forming protein gasdermin D to trigger pyroptosis in macrophages, whether RIPK1 activates additional substrates downstream of caspase-8 to promote host defense is unclear. Here, we report that the related gasdermin family member gasdermin E (GSDME) is activated upon detection of YopJ activity in a RIPK1 kinase-dependent manner. Specifically, GSDME promotes neutrophil pyroptosis and IL-1β release, which is critical for anti-Yersinia defense. During in vivo infection, IL-1β neutralization increases bacterial burden in wild-type but not Gsdme-deficient mice. Thus, our study establishes GSDME as an important mediator that counteracts pathogen blockade of innate immune signaling.

Keywords: RIPK1; Yersinia; caspases; gasdermin; neutrophils.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Cytokines / metabolism
  • Host-Pathogen Interactions / immunology
  • Immunity, Innate*
  • Interleukin-1beta / metabolism
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / metabolism*
  • Neutrophils / metabolism*
  • Pyroptosis
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Yersinia pseudotuberculosis / physiology*
  • Yersinia pseudotuberculosis Infections / immunology
  • Yersinia pseudotuberculosis Infections / microbiology


  • Cytokines
  • Gsdma protein, mouse
  • Interleukin-1beta
  • Neoplasm Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse