GBPs Inhibit Motility of Shigella flexneri but Are Targeted for Degradation by the Bacterial Ubiquitin Ligase IpaH9.8

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.

Sensing of invading pathogens by GBPs: At the crossroads between cell-autonomous and innate immunity

“…A transposon‐insertion library screening then identified that the bacterial secreted effector IpaH9.8, a E3 ubiquitin ligase, was responsible for causing hGBP1 degradation, as well as the degradation of hGBP2, 4, and 6, as well as mGBP2, 3, 6, 7, 9, 10, and 11 . A role for IpaH9.8 in degrading hGBPs was independently confirmed by Wandel et al., who also showed that this restores actin‐dependent bacterial motility and cell‐to‐cell spread . Finally, Li el al .…”

The species-spanning family of LPX-motif harbouring effector proteins

“…Poly-ubiquitinylation of NEMO leads to its degradation in a proteasome-dependent manner, thereby dampening NF-κB activation (Ashida et al, 2010). Recently, several independent studies found that IpaH9.8 is implicated in IFN-induced antimicrobial defences and counteracts cell-autonomous immunity mediated by the family of GBPs (guanylate-binding proteins; Li et al, 2017;Piro et al, 2017;Wandel et al, 2017). Upon invasion into human IFNγ-activated cells, S. flexneri is initially targeted by human GBP1 (hGBP1), which recognises cytosol-invading Gram-negative bacteria via the LPS O-antigen and then promotes the hierarchical recruitment of additional GBP paralogs.…”

“…Furthermore, it was found that IpaH9.8 synthesises a ubiquitin‐coat on S . flexneri , which in contrast to the host‐generated ubiquitin coat does not have antimicrobial effects on the cytosolic bacteria but rather supports the pathogen, possibly through antagonising GBP recruitment (Wandel et al, ). All in all, these studies point out that targeting of GBPs by IpaH9.8 is a prerequisite for S .…”

Demarcation of Viral Shelters Results in Destruction by Membranolytic GTPases: Antiviral Function of Autophagy Proteins and Interferon‐Inducible GTPases

“…In addition to their dynamin‐like function, these GTPases have more recently been appreciated to have a multitude of roles within cell‐autonomous defenses. GBPs are also known to bring various anti‐microbial effector proteins or to stunt bacterial spread by blocking bacterial association with actin . Furthermore, GBPs can enhance inflammasome formation, which produces inflammatory cytokines in response to pathogen invasion and cellular damages …”