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Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome

Nature volume 513, pages 237–241 (2014)Cite this article

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Abstract

Cytosolic inflammasome complexes mediated by a pattern recognition receptor (PRR) defend against pathogen infection by activating caspase 1. Pyrin, a candidate PRR, can bind to the inflammasome adaptor ASC to form a caspase 1-activating complex1,2. Mutations in the Pyrin-encoding gene, MEFV, cause a human autoinflammatory disease known as familial Mediterranean fever3,4,5. Despite important roles in immunity and disease, the physiological function of Pyrin remains unknown. Here we show that Pyrin mediates caspase 1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB6,7,8, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhoea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases (Vibrio parahaemolyticus VopS and Histophilus somni IbpA) and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the Pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. We further demonstrate that Burkholderia cenocepacia inactivates RHOA by deamidating Asn 41, also in the switch-I region, and thereby triggers Pyrin inflammasome activation, both of which require the bacterial type VI secretion system (T6SS). Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a new paradigm in mammalian innate immunity.

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Figure 1: Inflammasome activation by TcdB and identification of Pyrin as the candidate immune sensor.
Figure 2: Pyrin mediates TcdB-induced inflammasome activation.
Figure 3: Pyrin is required for TcdB-induced inflammasome activation.
Figure 4: Switch-I modification of the Rho subfamily accounts for Pyrin activation by TcdB and other Rho-modifying toxins.
Figure 5: T6SS-dependent Asn 41 deamidation of RHOA by B. cenocepacia activates the Pyrin inflammasome.

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Acknowledgements

We thank V. Dixit for providing knockout mice and anti-ASC antibody, D. Lyras for C. sordellii genomic DNA, J. Xiao for IbpA-Fic constructs, T. Iida for V. parahaemolyticus strain, M. Valvano for pDAI-SceI vector and H. Feng for TcdB B. megaterium expression system. We thank members of the Shao laboratory for discussions. The research was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute to F.S. This work was also supported by the National Basic Research Program of China 973 Program (2012CB518700), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08020202) and China National Science Foundation Program for Distinguished Young Scholars (31225002) to F.S.

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Author notes

  1. Hao Xu and Jieling Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. National Institute of Biological Sciences, Beijing, 102206, China

    Hao Xu, Jieling Yang, Wenqing Gao, Lin Li, Peng Li, Li Zhang, Yi-Nan Gong, Xiaolan Peng, She Chen, Fengchao Wang & Feng Shao

  2. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Jieling Yang & Feng Shao

  3. Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China

    Jianzhong Jeff Xi

  4. National Institute of Biological Sciences, Beijing, Collaborative Innovation Center for Cancer Medicine, Beijing, 102206, China

    Feng Shao

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Contributions

F.S. conceived the study; H.X. and J.Y. performed the majority of experiments, assisted by W.G.; L.L., P.L., L.Z., Y.-N.G., X.P., J.J.X., S.C. and F.W. contributed reagents and analytic tools. H.X., J.Y. and F.S. analysed the data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Feng Shao.

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Extended data figures and tables

Extended Data Figure 1 TcdB-induced caspase 1 inflammasome activation in various mouse BMDMs.

a–d, BMDMs from wild-type (WT, C57BL/6) or indicated knockout mice were left untreated (cont) or stimulated with TcdB, TcsL or EprI for 2.5 to 3 h. EprI was delivered by the LFn-PA system. e–g, Wild-type or Nod1−/− BMDMs (C57BL/6 background) or Nod1−/− BMDMs transfected with Nod2-specific siRNAs (Nod2-1 and Nod-2) or control siRNA were stimulated TcdB as indicated. The knockdown efficiency were measured by qRT–PCR analyses in f (n = 3; mean ± s.d.). h, BMDMs from different mouse inbred strains were stimulated with TcdB. TcdBm and TcsLm denote the glucosyltransferase-deficient TcdB(W102A/D288N) and TcsL(D286N/D288N) mutants, respectively. Macrophage supernatants were collected for anti-caspase 1 immunoblotting analyses in a, e, g and h (representative of at least three repetitions). ELISA assay of IL-1β release in LPS-primed BMDMs is shown in d and percentages of cell death measured by LDH (lactate dehydrogenase) release are in b, c (n = 3; mean ± s.d.).

Extended Data Figure 2 Cell rounding induced by Rho-modifying toxins and effectors.

Caspase 1−/− BMDMs were left untreated (control) or stimulated with large clostridial glucosylating cytotoxins TcdB/TcsL in a and FIC-domain bacterial effectors (VopS and IbpA-Fic1/2) in b. TcdBm and TcsLm denote the corresponding catalytically inactive mutants. VopS, IbpA-Fic1 and IbpA-Fic2 (WT or the catalytically inactive H/A mutants) were delivered into BMDMs using the LFn-PA system. Representative differential interference contrast (DIC) microscopy images of cell morphology are shown.

Extended Data Figure 3 TcdB-induced caspase 1 inflammasome activation in Pyrin-complemented DC2.4 cells and human monocyte-derived macrophages.

a–c, DC2.4 cells harbouring a vector (DC2.4+Vec), mouse Pyrin isoform 1 (DC2.4+mPyrin-iso1), mouse Pyrin isoform 2 (DC2.4+mPyrin-iso2), human Pyrin isoform 1 (DC2.4+hPyrin-iso1) or NLRP3 were stimulated with TcdB or as indicated. d–f, Phorbol-12-myristate-13-acetate (PMA)-differentiated THP-1 or U937 cells (harbouring a vector or human Pyrin isoform 1) were stimulated with TcdB or MxiH. g, qRT–PCR measurements of relative Pyrin expression level (normalized to that of GAPDH) (n = 3; mean ± s.d.). h, DC2.4 cells stably expressing eGFP–Pyrin were stimulated with TcdB or poly(dA:dT), and then subjected to anti-ASC immunofluorescence staining. DAPI stains the nuclei. The merged images show the co-aggregation of eGFP–Pyrin with endogenous ASC. Representative caspase 1 immunoblots from at least three repetitions are shown in c and d. ELISA assay of IL-1β release in a and percentages of cell death measured by LDH release in b, e and f are mean ± s.d. (n = 3).

Extended Data Figure 4 TALEN-mediated Mefv knockout in mice and its effect on TcdB-induced caspase 1 activation.

a, The design of Mefv-targeting TALEN. b, The sequence mutations for the five homozygous F1 lines used in the study. F1-1, 3 and 4 were obtained by intercross of two heterozygous founders bearing different frameshift alleles. F1-2 and 5 were crossed from another two heterozygous founders harbouring the same frameshift allele. c, BMDMs from Mefv−/− F1-3 and F1-4 mice were stimulated with TcdB or TcdBm. Shown are representative caspase 1 immunoblots from at least three repetitions.

Extended Data Figure 5 Toxins-induced modification of Rho GTPases and Rho inactivation by TcdB, TcsL, C3 and B. cenocepacia infection.

a, Lysates of TcdB or TcsL-treated Caspase 1−/− BMDM cells were subjected to in vitro ADP-ribosylation reaction by purified C3 toxin. Anti-RHOA immunoblotting shows TcdB modification of RHOA, as suggested by its resistance to further modification by the C3 toxin. b, c, e, DC2.4 cells were stimulated with TcdB, TcsL or LFn-tagged C3 toxin in b, c, or infected with B. cenocepacia (WT or the Δhcp mutant) in e. Cell lysates were subjected to glutathione S-transferase (GST)–RBD (the Rho binding domain of human Rhotekin protein) (b, e) and GST-PBD (the Rac/Cdc42 (p21) binding domain of human p21 activated kinase 1 protein (c, e) pulldown assays to measure GTP-bound RHOA and Rac/Cdc42, respectively. d, Caspase 1−/− BMDMs were delivered with V. parahaemolyticus VopS and the two FIC domains in H. somni IbpA (IbpA-Fic1/2) by the LFn-PA system. H/A, mutation of the FIC-domain catalytic histidine. Anti-RHOA immunoblotting shows the SDS–PAGE mobility shift of RHOA as a result of effector-catalysed adenylylation. Data in all panels are representative of at least three repetitions.

Extended Data Figure 6 Actin polymerization-inhibiting agents and the RID domain of Vibrio RTX toxin cannot activate caspase 1 inflammasome.

a, b, Primary BMDMs were left untreated (control), treated with cytochalasin D (Cyto D) or delivered with LFn-tagged actin crosslinking domain (ACD) from Vibrio RTX toxin. c–e, Primary BMDMs or Pyrin-complemented DC2.4 or 293T cells were stimulated with LFn-tagged RID domain from V. cholerae RTX toxin or TcdB. Representative DIC microscopy images of cell morphology are shown in a. Caspase 1 immunoblots are shown in b and c; percentages of cell death measured by LDH release are in d (n = 3; mean ± s.d.). Fluorescence images of RFP–ASC stably expressed in 293T cells are presented in e. Data in all panels are representative of at least three repetitions.

Extended Data Figure 7 Pyrin inflammasome activation by FIC-domain Rho-adenylylating effectors.

a, b, Effects of Nlrp3, Nlrc4 and Asc knockout on inflammasome activation by FIC-domain Rho-adenylylating effectors. c, d, BMDMs from wild-type mice or two independent Mefv−/− lines (F1-1 and F1-5) were stimulated with various FIC-domain effectors. e, f, Pyrin-complemented DC2.4 cells or primary BMDMs from wild-type or Mefv−/− F1-1 mice were stimulated with indicated toxins or infected with V. parahaemolyticus (V. para) POR3 strain (ΔtdhASΔvcrD2). VopS and IbpA-Fic1/2 were delivered into indicated BMDMs by the LFn-PA system. H/A, mutation of the catalytic histidine. Representative caspase 1 immunoblots from at least three repetitions are shown in a, e and f. ELISA assay of IL-1β release is in b, c, d (n = 3; mean ± s.d.).

Extended Data Figure 8 C3 modification/inactivation of the Rho subfamily induces Pyrin inflammasome activation.

C3 toxin was delivered into indicated BMDMs in a, c–e or DC2.4 cells stably expressing Flag–RHOA/Cdc42 in b by using the LFn-PA system. The SDS–PAGE mobility shift in anti-RHOA/Cdc42 immunoblots in a shows the specific modification of RHOA by C3. Flag–RHOA/Cdc42 purified from DC2.4 cells was subjected to TcdB glucosylation in the presence of UDP-[3H]Glucose. 3H-autoradiograph and anti-Flag immunoblot in b show that C3 stimulation blocks TcdB modification of RHOA but not Cdc42. Caspase 1 immunoblots are shown in c; ELISA assay of IL-1β release in LPS-primed BMDMs is in d and e (n = 3; mean ± s.d.). Data in all panels are representative of at least three repetitions.

Extended Data Figure 9 Pyrin requires, but does not directly interact with, the Rho subfamily in mediating TcdB-induced inflammasome activation.

a–d, Effects of siRNA knockdown of RHOA, B and C on TcdB-induced ASC foci formation. 293T cells stably expressing Pyrin and RFP–ASC were transfected with indicated siRNA or siRNA combinations followed by TcdB stimulation. Rhoa-1/2, Rhob-1/2 and Rhoc-1/2 are two independent siRNAs targeting RHOA, B and C, respectively. qRT–PCR analyses of the knockdown efficiency are shown in a, c (n = 3; mean ± s.d.) and percentages of cells showing ASC foci formation are in b, d (n = 3, mean ± s.d.; P value, Student’s t-test). e, f, Co-immunoprecipitation interaction assays of Pyrin and Rho GTPases. 293T cells were transfected with haemagglutinin (HA)–6myc–PyrinΔN88 (deletion of N-terminal 88 residue.) together with Flag–6myc–PyrinΔN88 or an indicated Rho GTPase construct in e. DC2.4 cells stably expressing Flag–6myc–PyrinΔN88 were left untreated or stimulated with TcdB in f. Immunoblots of anti-Flag immunoprecipitates (Flag IP) and total cell lysates (input) shown in e and f are representative from at least three repetitions.

Extended Data Figure 10 Pyrin senses B. cenocepacia-induced Asn 41 deamidation of RHOA and induces caspase 1 inflammasome activation in the T6SS-dependent manner.

a–e, Wild-type, Nlrp3−/−Nlrc4−/−, Aim2−/−, Asc−/− and Mefv−/− BMDMs were infected with B. cenocepacia J2315 strain (B.c., wild-type or the Δhcp mutant) or S. typhimurium (S.t.) for 3 h at a multiplicity of infection (m.o.i.) of 20:1. f–i, U937 or DC2.4 cells harbouring a vector or expressing human Pyrin (hPyrin) or mouse Pyrin isoform 1 (mPyrin-iso1) were infected with B. cenocepacia (B.c.) (wild type or the Δhcp mutant), S. flexneri (S.f.), EHEC, or stimulated with TcdB as indicated. j, Effects of overexpression of deamidated RHOA on ASC foci formation. The RHOA, B and C triple-knockdown 293T cells obtained in Fig. 4e were transiently transfected with an empty vector or a plasmid overexpressing RHOA wild type or the N41D mutant. Representative caspase 1 immunoblot from at least three repetitions are shown in a, b, e, f, h and i. ELISA assay of IL-1β release in c, d and g and percentages of cells showing the ASC foci in j are mean ± s.d. (n = 3). For j, the P value was determined by Student’s t-test.

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Xu, H., Yang, J., Gao, W. et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513, 237–241 (2014). https://doi.org/10.1038/nature13449

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