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Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence

Abstract

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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Figure 1: Transposon screen in S. flexneri identifies IpaH9.8 that mediates ubiquitin-proteasomal degradation of hGBP1.
Figure 2: IpaH9.8 directly recognizes and ubiquitinates hGBP1 in vitro and during infection.
Figure 3: GTP hydrolysis and farnesylation are required for hGBP1 translocation to S. flexneri but are not required for cytoplasmic degradation by IpaH9.8.
Figure 4: Targeting of GBPs by IpaH9.8 is required to counteract restriction of S. flexneri replication in mouse macrophages by GBPs.
Figure 5: IpaH9.8 suppresses GBPs-mediated defence in S. flexneri-infected mice.

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Acknowledgements

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).

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Authors and Affiliations

Authors

Contributions

P.L. and F.S. conceived the study; P.L., assisted by W.J., designed and performed the majority of the experiments; Q.Y. helped with protein purification. W.L. established SunTag labelling of T3SS effectors. W.J. and J.L. identified the substrate recognition-deficient mutations in IpaH9.8. B.X. and F.W. were involved in generating Gbpchr3 mice. P.Z. and J.X. provided technical assistance. P.L. and F.S. analysed the data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Feng Shao.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks R. Isberg, J. MacMicking and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Rapid proteasomal degradation of hGBP1 by the T3SS of S. flexneri.

a, b, HeLa cells stably expressing GFP–hGBP1 and mCherry–Gal3 were infected with S. flexneri (wild-type or ΔmxiH mutant) or wild-type S. Typhimurium. Representative time-lapse images of GFP and mCherry fluorescence after infection (scale bar, 20 μm).Supplementary Videos 1 and 2 are corresponding videos for wild-type S. flexneri and S. Typhimurium infection, respectively. c, d, HeLa cells stably expressing GFP or GFP-hGBP1 were infected with S. flexneri or other indicated bacterial pathogens. Y. enterocolitica ΔHOPEM is a MRS40 strain-derived mutant deficient in five T3SS effectors. d, Infections were performed in the absence or presence of MG132 (50 μg ml−1). Cell lysates collected at indicated time points after infection were immunoblotted with GFP antibody. All data shown are representative of three independent experiments.

Extended Data Figure 2 Transposon screen in S. flexneri identifies IpaH9.8, which mediates hGBP1 degradation; profiling of the specificity of anti-mGBP2 antibody.

a, The S. flexneri transposon screen for mutants defective for induction of hGBP1 degradation in HeLa cells stably expressing GFP–hGBP1 and mCherry–Gal3. b, Scatter plot of the fluorescence intensities of all the 96 wells in a representative plate (#103). The x and y axes show the intensity of mCherry and GFP fluorescence, respectively. G11 (red) is the no-infection control. The green points clustered with G11 are candidate hits. c, Fluorescence images of the candidate hits in b. d, Immunofluorescence with mGBP2 antibody. HeLa cells were transfected with the indicated GFP-tagged mGBP constructs. Cells were fixed 12 h after transfection. Scale bar, 10 μm. Data in c, d are representative of two independent experiments.

Extended Data Figure 3 IpaH9.8 degrades hGBP1 more rapidly than NEMO, and is the only IpaH-family member that can degrade hGBP1.

a, b, Comparison of the degradation of endogenous hGBP1 and hGBP2 with that of NEMO by IpaH9.8. IFNγ-primed HeLa cells were infected with wild-type S. flexneri or ΔipaH9.8 mutant (a) or S. flexneri expressing IpaH9.8 or IpaH9.8-M3 (b). Cell lysates collected at indicated time points after start of the infection were immunoblotted as shown. c, HeLa cells stably expressing GFP–hGBP1 were transfected with the indicated mCherry–IpaH constructs. Fluorescence images were taken 24 h after transfection. Scale bar, 10 μm. d, IFNγ-primed HeLa cells were transfected with the indicated 6×Myc–IpaH constructs or IpaH9.8-C337A. Lysates were immunoblotted as shown. All data shown are representative of three independent experiments.

Extended Data Figure 4 IpaH9.8 directly targets hGBP1 for K48-linked polyubiquitination on multiple lysine residues.

a, Lysates of 293T cells co-transfected with Flag–hGBP1 and Myc–IpaH9.8, Myc–IpaH3 or Myc–IpaH7.8 were immunoprecipitated with Flag antibody and immunoblotted as shown. Synthetic Lys48 (K48)- and Lys63 (K63)-linked ubiquitin chains or linear tetra-ubiquitin were included as controls for the linkage-specific antibodies. b, Gel filtration chromatography of purified hGBP1 and IpaH9.8. Coomassie blue-stained SDS–PAGE gel of fractions eluted from the Superdex 200 column. c, Effects of overexpression of mCherry–IpaH9.8-C337A on GFP–hGBP1 recruitment to intracellular S. flexneri ΔipaH9.8 in HeLa cells. Fluorescence images taken 2 h after infection (nearly all cells were successfully infected by the bacteria). Scale bar, 10 μm. d, In vitro ubiquitination of hGBP1 by IpaH9.8 and other IpaH-family proteins. Coomassie blue-stained SDS–PAGE gel shows the Flag–hGBP1 and IpaH proteins added to the reaction. e, f, Ubiquitination sites in hGBP1. The lysine residues indicated in e, except for Lys207 and Lys209, were identified by mass spectrometry analyses of in vitro ubiquitinated hGBP1 (the seven residues labelled in red were identified after the other labelled residues were mutated to arginine (8KR)). 15KR is a mutant hGBP1 in which all fifteen lysine residues have been replaced with arginine. f, 293T cells were co-transfected with Flag–hGBP1 (WT, 8KR or 15KR) and 6×Myc–IpaH9.8. Cell lysates were immunoprecipitated with Flag antibody and the immunoprecipitates were immunoblotted as shown. C/A, hGBP1-C337A. All data shown are representative of three independent experiments.

Extended Data Figure 5 The LRR domain in IpaH9.8 mediates hGBP1 binding that is independent of the nucleotide-bound states of hGBP1.

a, c, d, Gel filtration chromatography analyses of in vitro complex formation between the LRR domain of IpaH9.8 and hGBP1 (a) and between IpaH9.8 and wild-type (c), R48A or D184N mutant (d) hGBP1. Purified hGBP1 was pre-incubated with GMP, GDP, GppNHp, or GDP–AlFx. b, Flag–IpaH9.8 and haemagglutinin (HA)-tagged hGBP1 or hGBP5 were co-expressed in 293T cells. Lysates were immunoprecipitated with Flag antibody (Flag IP), and immunoblotted as shown. e, In vitro ubiquitination of the R48A, D184N and C589S mutants of hGBP1 by IpaH9.8. All data shown are representative of three independent experiments.

Extended Data Figure 6 IpaH9.8 targets multiple GBPs for degradation.

a, b, HeLa cells stably expressing a GFP-tagged GBP-family member of human (a) or mouse (b) origin were infected with S. flexneri (WT or ΔipaH9.8). Cell lysates collected at the indicated time points after infection were immunoblotted with GFP and tubulin antibodies. GBPs that show IpaH9.8-dependent degradation are labelled in bold. c, d, 293T cells were co-transfected with 6×Myc–IpaH9.8 and a Flag-tagged GBP-family member from human (c) or mouse (d). Cell lysates were immunoprecipitated with Flag antibody and immunoblotted with Myc antibody as shown. C/A, hGBP1-C337A. All data shown are representative of three independent experiments.

Extended Data Figure 7 Differential sensitivity of GBP family members to IpaH9.8-mediated degradation and translocation to S. flexneri.

ac, HeLa cells stably expressing a GFP-tagged human (a, c) or mouse (b) GBP-family member were infected with mCherry-labelled S. flexneri (wild-type or ΔipaH9.8). a, b, Fluorescence images taken 2 h after infection (scale bar, 10 μm). c, Cells were primed with IFNγ, and cells containing GBP-decorated S. flexneri ΔipaH9.8 were counted. Approximately 200 infected cells were examined for each infection and data are expressed as mean percentages ± s.d. from three technical replicates. All data shown are representative of two independent experiments.

Source data

Extended Data Figure 8 Binding and ubiquitination of different GBP-family members by IpaH9.8.

a, b, 293T cells were co-transfected with Flag–IpaH9.8-C337A and a haemagglutinin-tagged human (a) or mouse (b) GBP-family member. c, In vitro ubiquitination of Flag-tagged representative GBP-family members by IpaH9.8. d, The haemagglutinin-tagged GTPase domain (N) or helical domain (C) of the indicated GBP proteins was co-transfected with Flag–IpaH9.8-C337A or Flag–RFP control into 293T cells. e, Haemagglutinin-tagged mGBP1, mGBP2, or the indicated chimaera construct, were co-transfected with 6×Myc–IpaH9.8 (wild-type or C337A mutant (C/A)) or a vector control (−) into 293T cells. 1N, GTPase domain of mGBP1; 2N, GTPase domain of mGBP2; 1C, helical domain of mGBP1; 2C, helical domain of mGBP2. Cell lysates (a, b, d) or reaction mixtures (c) were immunoprecipitated with Flag antibody (Flag IP) and immunoblotted with Flag, haemagglutinin, tubulin or myc antibodies. Coomassie blue-stained SDS–PAGE gels (c) show the recombinant proteins added into the reaction. All data shown are representative of two independent experiments.

Extended Data Figure 9 Point mutations in the LRR domain of IpaH9.8 that affect binding of GBPs mitigate IpaH9.8 disruption of GBP function in vivo.

a, b, HeLa cells stably expressing GFP–hGBP1 were infected with indicated S. flexneri strains. The ΔipaH9.8 strain was complemented with wild-type IpaH9.8 or the L50A, R62A, or N83A single mutant (a), or the M3 triple mutant (a, b). Cell lysates collected at indicated time points after the infection were immunoblotted with GFP and tubulin antibodies (a). Fluorescence images were taken 2 h after infection (b). c, Assay of secretion of IpaH9.8-M3 in host cells. HeLa cells were infected with S. flexneri ΔipaH9.8 expressing β-lactamase (TEM1) alone or TEM1-fused IpaH9.8 (wild-type or M3 mutant). Infected cells were loaded with the CCF2–AM dye; the 460-nm fluorescence emission of the dye indicates translocation of TEM1 from the bacteria into HeLa cell cytoplasm. d, Ubiquitin-ligase activity of IpaH9.8-M3 in synthesizing free ubiquitin chains. Immunoblot of the substrate-free ubiquitin reaction with ubiquitin antibody. e, In vitro ubiquitination of mGBP2 by IpaH9.8 or the indicated IpaH9.8 mutant proteins. Flag–mGBP2 was added to the reaction mixtures, which were then immunoprecipitated with Flag antibody followed by immunoblotting with ubiquitin antibody. Coomassie blue-stained SDS–PAGE gels show the recombinant proteins added into the reaction. f, Recruitment of endogenous mGBP2 onto intracellular S. flexneri. BMDMs from Casp1−/−Casp11−/− or Gsdmd−/−Gbpchr3 mice were infected with S. flexneri WT, ΔipaH9.8 or ΔipaH9.8 expressing IpaH9.8-M3. Infected cells were fixed 2 h after infection (a time point when bacterial morphology change had not occurred) and stained with DAPI and mGBP2 antibody. Representative fluorescence images are shown (scale bar, 3 μm). Note that while the mGBP2 antibody may cross-react with mGBP1 (Extended Data Fig. 2d), we believe that the anti-mGBP2 immunofluorescence detected on the Shigella surface here should mainly reflect mGBP2 for three reasons. First, GFP–mGBP1 could not translocate to the bacterial surface in Shigella-infected HeLa cells (Extended Data Fig. 7b). Second, mGBP1 is not a degradation target of IpaH9.8 (Extended Data Fig. 6b, 6d and 8b–e), but appearance of the mGBP2 immunofluorescence in this assay was fully responsive to the presence of IpaH9.8 in S. flexneri. Third, as shown here, the mGBP2 immunofluorescence signal was absent in Gbpchr3 BMDMs infected with S. flexneri ΔipaH9.8. However, we cannot completely rule out the possibility that the mGBP2 fluorescence signal detected on the Shigella surface contains a small fraction of mGBP1 if mGBP1 can dimerize with mGBP2 and therefore be recruited to the bacterial surface. g, h, BMDMs from Casp1−/−Casp11−/− mice were infected with wild-type S. flexneri or the indicated ipaH9.8 deletion or complementation strain for 4 h. Representative images of cytoplasmic S. flexneri indicated by anti-Shigella LPS staining (g). Nuclei are stained with DAPI. Scale bar, 3 μm (upper) and 1.5 μm (lower). h, Quantification of cytoplasmic bacteria with aberrant morphology. Approximately 100 infected cells were examined for each experiment and data are represented as mean percentages ± s.d. from three replicates. Two-tailed unpaired Student’s t-test was performed (**P ≤ 0.0001). All data shown are representative of two (b, c, fh) or three (a, d, e) independent experiments.

Source data

Extended Data Figure 10 Generation of Gbpchr3 mice by CRISPR/Cas9-mediated genome editing and analyses of its functional connection with ipaH7.8.

a, The Gbp locus on mouse chromosome 3 and the genomic RNA targeting strategy for generating the knockout mice. b, Genome typing of founder mice by PCR. +/+, +/− and −/− denote mice with wild-type Gbp locus, one copy of the Gbp locus deleted and both copies of the Gbp locus deleted, respectively. Chromosomal location of the four PCR primers used for genome typing are shown in a. c, Junction sequences of two types of Gbpchr3 deletion alleles, determined by DNA sequencing of the PCR products in b. Mice used in this study are homologous for one of the two out-of-frame alleles or heterozygous for the two alleles. dg, Wild-type or Gbpchr3 mice (C57BL/6 background) were infected with S. flexneri ΔipaH7.8 intravenously (d, e) or intraperitoneally (f, g) at MOI of 2 × 106 or 4 × 106, respectively. Mouse survival analysis (d, f) was performed in GraphPad Prism 5. Bacterial loads 1 day after infection (e, g) are expressed as log10 colony-forming units per gram of liver or spleen tissue; mean values are also shown. Sample sizes (biologically independent animals): n = 10 for both groups in d, n = 7 for both groups in e, n = 12 for both groups in f, n = 7 for WT/ΔipaH7.8 and n = 6 for Gbpchr3ipaH7.8 in g. Data shown are representative of three (b) or two (dg) independent experiments.

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Supplementary information

Supplementary Information

This file contains the uncropped immunoblots for key data presented in the paper. (PDF 7880 kb)

Reporting Summary (PDF 68 kb)

Rapid degradation of cellular hGBP1 by S. flexneri infection

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. (MOV 2021 kb)

No degradation of cellular hGBP1 by S. Typhimurium infection

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. (MOV 1985 kb)

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Li, P., Jiang, W., Yu, Q. et al. Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence. Nature 551, 378–383 (2017). https://doi.org/10.1038/nature24467

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