Cell Host Microbe 22, 507–518 (2017) Nature doi:10.1038/nature24467 (2017)

Credit: NATURE

Cell-autonomous innate immune functions, such as recruitment of a family of interferon-stimulated GTPases, GBPs, to the surface of intracellular bacteria, protect mammalian cells from invading pathogens. Two studies now establish that the surface of the intracellular pathogen Shigella flexneri is coated with host GBPs. Explaining how S. flexneri can persist intracellularly, these studies showed that GBP1 was degraded by proteasomes upon S. flexneri infection and that this degradation was dependent on a type III secretion system (T3SS). Screening of a transposon-insertion library identified a mutation in the gene encoding the T3SS effector and the E3 ligase IpaH9.8 that failed to cause GBP1 degradation. Wandel et al. found that upon interferon stimulation, S. flexneri bacteria could not produce actin tails, which are required for bacterial motility and for transmission between host cells, and that the bacteria were decorated with polyubiquitin chains, as well as GBPs. Both studies showed that IpaH9.8 mutant bacteria maintained the GBP coat within host cells and validated IpaH9.8-mediated GBP ubiquitylation in vitro and proteasomal degradation in cells. Functionally, Wandel et al. found that GBPs restrict actin-driven motility, and Li et al. showed that GBPs reduce proliferation and bacterial load; both can be reversed by IpaH9.8. Finally, Li et al. found that in a mouse infection model, IpaH9.8 mediates degradation of GBPs and infectivity of S. flexneri. These results define a clever bacterial defense against a host-derived effector mechanism designed to thwart intracellular bacteria.