Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death
Daniel Fisch,
Barbara Clough,
Marie-Charlotte Domart,
Vesela Encheva,
Hironori Bando,
Ambrosius P. Snijders,
Lucy M. Collinson,
Masahiro Yamamoto,
Avinash R. Shenoy,
Eva-Maria Frickel
Affiliations
Daniel Fisch
Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London NW1 1AT, UK; MRC Centre for Molecular Bacteriology & Infection, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK
Barbara Clough
Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London NW1 1AT, UK
Marie-Charlotte Domart
Electron Microscopy Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK
Vesela Encheva
Mass Spectrometry and Proteomics Platform, The Francis Crick Institute, London NW1 1AT, UK
Hironori Bando
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Ambrosius P. Snijders
Mass Spectrometry and Proteomics Platform, The Francis Crick Institute, London NW1 1AT, UK
Lucy M. Collinson
Electron Microscopy Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK
Masahiro Yamamoto
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Avinash R. Shenoy
MRC Centre for Molecular Bacteriology & Infection, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK; The Francis Crick Institute, London NW1 1AT, UK; Corresponding author
Eva-Maria Frickel
Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK; Corresponding author
Summary: Interferon-inducible guanylate-binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles and promote membrane disruption for release of microbial molecules that activate inflammasomes. GBP1 mediates pyroptosis or atypical apoptosis of Salmonella Typhimurium (STm)- or Toxoplasma gondii (Tg)- infected human macrophages, respectively. The pathogen-proximal detection-mechanisms of GBP1 remain poorly understood, as humans lack functional immunity-related GTPases (IRGs) that assist murine Gbps. Here, we establish that GBP1 promotes the lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm and recruits caspase-4 to the bacterial surface for its activation by lipopolysaccharide (LPS), but does not contribute to bacterial vacuole escape. Caspase-1 cleaves and inactivates GBP1, and a cleavage-deficient GBP1D192E mutant increases caspase-4-driven pyroptosis due to the absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection detection and its triggering of the assembly of divergent caspase signaling platforms.
