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Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death.
- Source :
-
Cell reports [Cell Rep] 2020 Aug 11; Vol. 32 (6), pp. 108008. - Publication Year :
- 2020
-
Abstract
- 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 GBP1 <superscript>D192E</superscript> 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.<br />Competing Interests: Declaration of Interests The authors declare no competing interests.<br /> (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Death immunology
HEK293 Cells
Humans
Inflammasomes immunology
Interferon-gamma pharmacology
Ligands
Salmonella Infections immunology
Salmonella Infections microbiology
THP-1 Cells
Toxoplasma genetics
Toxoplasmosis immunology
Toxoplasmosis microbiology
Vacuoles immunology
Caspases immunology
GTP-Binding Proteins immunology
Salmonella typhimurium immunology
Toxoplasma immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 32
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 32783936
- Full Text :
- https://doi.org/10.1016/j.celrep.2020.108008