RT Journal Article
SR Electronic
T1 Differential spatiotemporal targeting of <em>Toxoplasma</em> and <em>Salmonella</em> by GBP1 assembles caspase signalling platforms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 792804
DO 10.1101/792804
A1 Daniel Fisch
A1 Barbara Clough
A1 Marie-Charlotte Domart
A1 Hironori Bando
A1 Tereza Masonou
A1 Lucy M Collinson
A1 Masahiro Yamamoto
A1 Avinash R Shenoy
A1 Eva-Maria Frickel
YR 2019
UL http://biorxiv.org/content/early/2019/10/05/792804.abstract
AB Human guanylate binding proteins (GBPs), a family of IFNγ-inducible GTPases, promote cell-intrinsic defence against pathogens and host cell death. We previously identified GBP1 as a mediator of cell death of human macrophages infected with Toxoplasma gondii (Tg) or Salmonella Typhimurium (STm). How GBP1 targets microbes for AIM2 activation during Tg infection and caspase-4 during STm infection remains unclear. Here, using correlative light and electron microscopy and EdU labelling of Tg-DNA, we reveal that GBP1-decorated parasitophorous vacuoles (PVs) lose membrane integrity and release Tg-DNA for detection by AIM2-ASC-CASP8. In contrast, differential staining of cytosolic and vacuolar STm revealed that GBP1 does not contribute to STm escape into the cytosol but decorates almost all cytosolic STm leading to the recruitment of caspase-4. Caspase-5, which can bind LPS and whose expression is upregulated by IFNγ, does not target STm pointing to a key role for caspase-4 in pyroptosis. We also uncover a regulatory mechanism involving the inactivation of GBP1 by its cleavage at Asp192 by caspase-1. Cells expressing non-cleavable GBP1D192E therefore undergo higher caspase-4-driven pyroptosis during STm infection. Taken together, our comparative studies elucidate microbe-specific spatiotemporal roles of GBP1 in inducing cell death by leading to assembly and regulation of divergent caspase signalling platforms.