Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells

Immunity. 2021 Jul 13;54(7):1447-1462.e5. doi: 10.1016/j.immuni.2021.04.012. Epub 2021 May 11.


Two sets of innate immune proteins detect pathogens. Pattern recognition receptors (PRRs) bind microbial products, whereas guard proteins detect virulence factor activities by the surveillance of homeostatic processes within cells. While PRRs are well known for their roles in many types of infections, the role of guard proteins in most infectious contexts remains less understood. Here, we demonstrated that inhibition of protein synthesis during viral infection is sensed as a virulence strategy and initiates pyroptosis in human keratinocytes. We identified the BCL-2 family members MCL-1 and BCL-xL as sensors of translation shutdown. Virus- or chemical-induced translation inhibition resulted in MCL-1 depletion and inactivation of BCL-xL, leading to mitochondrial damage, caspase-3-dependent cleavage of gasdermin E, and release of interleukin-1α (IL-1α). Blocking this pathway enhanced virus replication in an organoid model of human skin. Thus, MCL-1 and BCL-xL can act as guard proteins within barrier epithelia and contribute to antiviral defense.

Keywords: apoptosis; effector-triggered immunity; gasdermin; herpes simplex virus 1; innate immunity; keratinocytes; mitochondria; skin organoid; translation; vesicular stomatitis virus.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Apoptosis Regulatory Proteins / immunology
  • Caspase 3 / immunology
  • Cell Line
  • Chlorocebus aethiops
  • Epithelial Cells / immunology*
  • HEK293 Cells
  • Humans
  • Interleukin-1alpha / immunology
  • Mice
  • Mitochondria / immunology
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins c-bcl-2 / immunology*
  • Pyroptosis / immunology*
  • Receptors, Estrogen / immunology*
  • Vero Cells
  • Virus Replication / immunology
  • Viruses / immunology*
  • bcl-X Protein / immunology


  • Apoptosis Regulatory Proteins
  • GSDME protein, human
  • Interleukin-1alpha
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Estrogen
  • bcl-X Protein
  • Caspase 3