Abstract
SummaryInterferon exposure boosts cell-autonomous immunity for more efficient pathogen control. But how interferon-enhanced immunity protects the cytosol against bacteria and how professionally cytosol-dwelling bacteria avoid clearance are insufficiently understood. Here we demonstrate that the interferon-induced GTPase family of guanylate-binding proteins (GBPs) coats Shigella flexneri in a hierarchical manner reliant on GBP1. GBPs inhibit actin-dependent motility and cell-to-cell spread of bacteria but are antagonized by IpaH9.8, a bacterial ubiquitin ligase secreted into the host cytosol. IpaH9.8 ubiquitylates GBP1, GBP2, and GBP4 to cause the proteasome-dependent destruction of existing GBP coats. This ubiquitin coating of Shigella favors the pathogen as it liberates bacteria from GBP encapsulation to resume actin-mediated motility and cell-to-cell spread. We conclude that an important function of GBP recruitment to S. flexneri is to prevent the spread of infection to neighboring cells while IpaH9.8 helps bacterial propagation by counteracting GBP-dependent cell-autonomous immunity.
Highlights
Pathogens inhabit specific niches in their host organism to which they are exquisitely adapted
By studying the fate of S. flexneri in human cells activated with IFNg, we discovered that, in a hierarchical manner and dependent on GBP1, bacteria become coated with multiple guanylate-binding proteins (GBPs)
We found that the majority of GBP1- and GBP3-positive S. flexneri were coated with ubiquitin but that, importantly, only GBP1 occurred on all ubiquitin-coated bacteria (Figures 2H and S3)
Summary
Pathogens inhabit specific niches in their host organism to which they are exquisitely adapted. GBPs have been suggested to compromise the structural integrity of bacteria, to release ligands that stimulate inflammasomes, and to activate anti-bacterial effector mechanisms such as xenophagy and the oxidative burst (Kim et al, 2011; Man et al, 2016; Meunier et al, 2015). The target of GBP action remains hotly disputed since evidence has emerged for GBPs attacking host membranes as well as bacterial surfaces (Man et al, 2016; Meunier et al, 2014) It remains unknown whether individual GBPs perform specific functions or whether their action is largely redundant as suggested by mouse knockout experiments, in which phenotypes emerged only upon large chromosomal deletions encompassing several GBPs (Yamamoto et al, 2012)
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