Interferon-inducible guanylate-binding proteins (GBPs) mediate cell-autonomous antimicrobial defences1,2. Shigella flexneri, a Gram-negative cytoplasmic free-living bacterium that causes bacillary dysentery3, encodes a repertoire of highly similar type III secretion system effectors called invasion plasmid antigen Hs (IpaHs)4. IpaHs represent a large family of bacterial ubiquitin-ligases5,6,7,8, but their function is poorly understood. Here we show that S. flexneri infection induces rapid proteasomal degradation of human guanylate binding protein-1 (hGBP1). We performed a transposon screen to identify a mutation in the S. flexneri gene ipaH9.8 that prevented hGBP1 degradation. IpaH9.8 targets hGBP1 for degradation via Lys48-linked ubiquitination. IpaH9.8 targets multiple GBPs in the cytoplasm independently of their nucleotide-bound states and their differential function in antibacterial defence, promoting S. flexneri replication and resulting in the death of infected mice. In the absence of IpaH9.8, or when binding of GBPs to IpaH9.8 was disrupted, GBPs such as hGBP1 and mouse GBP2 (mGBP2) translocated to intracellular S. flexneri and inhibited bacterial replication. Like wild-type mice, mutant mice deficient in GBP1–3, 5 and 7 succumbed to S. flexneri infection, but unlike wild-type mice, mice deficient in these GBPs were also susceptible to S. flexneri lacking ipaH9.8. The mode of IpaH9.8 action highlights the functional importance of GBPs in antibacterial defences. IpaH9.8 and S. flexneri provide a unique system for dissecting GBP-mediated immunity.
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We thank L. Li, S. Chen, Y. Wang, Y. She, Y. Chen and Z. Yang for technical assistance, and M. Valvano, G. Cornelis, J. Mekalanos and A. Gilmore for reagents. The work was supported by the Basic Science Center Project of NSFC (81788104), the National Key Research and Development Program of China (2017YFA0505900 and 2016YFA0501500), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08020202).
Extended data figures
HeLa cells stably expressing GFP-hGBP1 and mCherry-Gal3 were infected with S. flexneri 2a strain 2457T. Shown are real-time videos of representative fields of the infected cells. Scale bar, 20 μm. The time-lapse images are in Extended Data Figure 1a.
HeLa cells stably expressing GFP-hGBP1 and mCherry-Gal3 were infected with S. Typhimurium strain SL1344. Shown are real-time videos of representative fields of the infected cells. Scale bar, 20 μm.
About this article
Current Opinion in Immunology (2019)