Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis

Daniel Fisch, Hironori Bando, Barbara Clough, Veit Hornung, Masahiro Yamamoto, Avinash R. Shenoy, Eva Maria Frickel

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The guanylate binding protein (GBP) family of interferon-inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 support the activation of caspase-1-containing inflammasome complexes or caspase-4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma-induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD-independent, ASC-, and caspase-8-dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella-containing vacuoles. GBP1 facilitated caspase-4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.

Original languageEnglish
Article numbere100926
JournalEMBO Journal
Volume38
Issue number13
DOIs
Publication statusPublished - 2019 Jul 1
Externally publishedYes

Keywords

  • Salmonella Typhimurium
  • Toxoplasma gondii
  • apoptosis
  • caspases
  • pyroptosis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Fisch, D., Bando, H., Clough, B., Hornung, V., Yamamoto, M., Shenoy, A. R., & Frickel, E. M. (2019). Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis. EMBO Journal, 38(13), [e100926]. https://doi.org/10.15252/embj.2018100926