Human GBP1 differentially targets salmonella and toxoplasma to license recognition of microbial ligands and caspase-mediated death
File(s)
Published version
Author(s)
Type
Journal Article
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 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.
Date Issued
2020-08-11
Date Acceptance
2020-07-15
Citation
Cell Reports, 2020, 32 (6), pp.1-22
ISSN
2211-1247
Publisher
Elsevier
Start Page
1
End Page
22
Journal / Book Title
Cell Reports
Volume
32
Issue
6
Copyright Statement
© 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sponsor
Wellcome Trust
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000560042600010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
108246/Z/15/Z
MR/P022138/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
GUANYLATE-BINDING-PROTEIN
CELL-AUTONOMOUS IMMUNITY
NONCANONICAL INFLAMMASOME ACTIVATION
INTERFERON-INDUCIBLE GTPASES
IRG RESISTANCE GTPASES
NLRP3 INFLAMMASOME
AIM2 INFLAMMASOME
HUMAN MACROPHAGES
HOST-DEFENSE
AUTOPHAGY
Publication Status
Published
Article Number
ARTN 108008
Date Publish Online
2020-08-11