Abstract
Gasdermins, a family of five pore-forming proteins (GSDMA–GSDME) in humans expressed predominantly in the skin, mucosa and immune sentinel cells, are key executioners of inflammatory cell death (pyroptosis), which recruits immune cells to infection sites and promotes protective immunity1,2. Pore formation is triggered by gasdermin cleavage1,2. Although the proteases that activate GSDMB, C, D and E have been identified, how GSDMA—the dominant gasdermin in the skin—is activated, remains unknown. Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a major skin pathogen that causes substantial morbidity and mortality worldwide3. Here we show that the GAS cysteine protease SpeB virulence factor triggers keratinocyte pyroptosis by cleaving GSDMA after Gln246, unleashing an active N-terminal fragment that triggers pyroptosis. Gsdma1 genetic deficiency blunts mouse immune responses to GAS, resulting in uncontrolled bacterial dissemination and death. GSDMA acts as both a sensor and substrate of GAS SpeB and as an effector to trigger pyroptosis, adding a simple one-molecule mechanism for host recognition and control of virulence of a dangerous microbial pathogen.
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Data availability
All data supporting the findings of this study are included in this manuscript and its supplementary information. Source data are provided with this paper.
Change history
27 July 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41586-022-05109-x
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Acknowledgements
We thank V. Nizet for sharing S. pyogenes isolate M1T1 strain 5448 and its isogenic mutant strains (ΔspeB, covR/S−, ΔcepA and Δmac variants) as well as SpeB constructs, Z. Zhang for providing S. pyogenes M9, M12 amd M73 strains, C. Wang for providing Phage-Flag vector, and Y. Chen for providing a modified pET vector with an N-terminal 6×His-SUMO tag. This work was supported by National Key R&D Program of China (2020YFA0509600), National Natural Science Foundation of China (32122034, 31972897), Key Research Program of the Chinese Academy of Sciences (ZDBS-LY-SM008), Shanghai Pilot Program for Basic Research–Chinese Academy of Sciences, Shanghai Branch (JCYJ-SHFY-2021-009), Strategic Priority Research Program of Chinese Academy of Sciences (XDB29030300), Shanghai Municipal Science and Technology Major Project (2019SHZDZX02) (X.L.), NIH R01CA240955 and R01AI39914 (J.L.), NIH R01AI127654 (T.S.K.) and China Postdoctoral Science Foundation (2019M650193), Guangzhou Science and Technology Project (202102020093) (W.D.).
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W.D., Y.B., F.D., Y.P., J.L. and X.L. conceived the study. W.D., Y.B., F.D. and Y.P. designed and performed most experiments with assistance from R. Min, Z.W. and W.L. Z. Zheng and S.M. performed the CRISPR screen and sequencing data analysis, respectively. R. Miao and Z. Zhang provided technical support. W.D., Y.B., F.D., Y.P. and X.L. analysed the data. All authors discussed the results and commented on the manuscript. W.D., Y.B., F.D., Y.P., T.S.K., J.L. and X.L. wrote the manuscript. X.L. supervised the study.
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Extended data figures and tables
Extended Data Fig. 1 SpeB-deficient GAS triggers systemic infection.
a, DNA sequence comparison of GAS isolate M1T1 strain 5448 and its isogenic mutant strains (ΔcepA, Δmac, covR/S− and ΔspeB variants). b, c, RT-PCR (b) and immunoblot analysis (c) of the expression of SpeB in the indicated GAS strains. d–f, mice were infected or not with the indicated GAS strains. d, IHC analysis of neutrophil infiltration at infection site on day 1. Scale bar: 100 μm. e, Bacteria load measured from skin lesions, spleens and livers of mice infected or not with GAS. f, Survival rate of mice challenged or not with the indicated GAS (n = 18 mice per group). e, box plots show all points, min to max (n = 5 mice per group). The center line, upper limit and lower limit of the box denote median, 25th and 75th percentiles and the whiskers denote the minimum and maximum values of data. e, Two-tailed Student’s t-test; f, Mantel-Cox log-rank test. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 2 SpeB contributes to local tissue destruction.
a, b, The re-expression of SpeB in ΔspeB GAS was confirmed by both RT-PCR (a) and immunoblot analysis (b). c–h, mice were infected or not with the indicated GAS strains. c, Representative image of skin lesions of mice challenged with GAS or not for 1 day. d, Quantification of skin lesion size. e, Histopathology of skin biopsies analysed by H&E staining. f, g, IHC analysis and quantification of neutrophil infiltration at infection site. h, Bacteria load measured from skin lesions, spleens and livers of mice infected or not with GAS. Scale bar: 100 μm. d, g, show mean ± s.d. (n = 5 mice per group); h, box plots show all points, min to max (n = 5 mice per group). The center line, upper limit and lower limit of the box denote median, 25th and 75th percentiles and the whiskers denote the minimum and maximum values of data. d, g, h, Two-tailed Student’s t-test. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 3 SpeB triggers lytic death of primary mouse keratinocytes and A431 cells.
a, Primary mouse keratinocytes were infected with GAS isolate M1T1 strain 5448 or its isogenic mutant strains for the indicated times. Percentage of internalized GAS was shown by counting intracellular CFUs relative to the inoculum (left panel). Cell cytotoxicity of all the cells in a well was measured by LDH release assay (right panel). b–d, Primary keratinocytes infected with FITC-labeled GAS strains were washed with PBS before cells were stained and analyzed by confocal fluorescence imaging. Cell borders are outlined with dashed lines. Cells with intracellular GAS were quantified from 700 cells (n = 5, mean ± s.d.) (b). e, Levels of hyaluronic acid capsule at logarithmic and stationary growth phases. f, RT-PCR (left panel) and immunoblot analysis (right panel) of the expression of SpeB in the indicated GAS strains. g, h Primary keratinocytes infected or not with the indicated GAS strains for 2.5 h were analysed by phase-contrast microscopy (g), LDH release (h). i, j, A431 cells infected or not with GAS isolate M1T1 strain 5448 or its isogenic mutant strains for 2.5 h were analysed by phase-contrast microscopy (i) and LDH release (j). k, l, Equal amounts of recombinant of WT SpeB or protease activity-deficient mutant mSpeB were respectively electroporated into A431 cells for 1 h or directly added into cell culture medium for 2.5 h, followed by cell morphology observation by phase-contrast microscopy (k), cell viability assessment by CellTiter-Glo luminescent assay (l). g, i, Arrowheads indicate pyroptotic cells. c, d, g, i, k, scale bar: 10 μm. Graphs show mean ± s.d. of triplicate wells. h, j, One-way ANOVA; l, Two-tailed Student’s t-test. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 4 Validation of additional hits identified from CRISPR screen of SpeB-triggered lytic cell death.
a, List of top hits from CRISPR screen of SpeB-triggered lytic cell death. b, GSDMA-knockout cells used in this study. Gene coding sequences were present as black boxes. Top sequence track is the gene wild-type allele. Location of gRNAs is indicated with blue bars and PAM sequences were underscored. c–l, WT and the indicated gene knockout A431 cells were transfected or not with recombinant SpeB by electroporation, followed by cell morphology observation by phase-contrast microscopy (c, e, g, i, k), cell viability assessment by CellTiter-Glo luminescent assay (d, f, h, j, l). Scale bar: 10 μm. Graphs show mean ± s.d. of triplicate wells. Data are representative of at least three independent experiments.
Extended Data Fig. 5 SpeB specifically targets and cleaves GSDMA.
a, b, In vitro cleavage assay of recombinant GSDMA, GSDMD (a) or GSDME (b) by incubation with recombinant WT SpeB (100 nM) or mSpeB (250 nM) for 0.5 h. c, Whole cell lysates of A431 cells infected or not with the indicated GAS strains were subjected to immunoblot analysis for the indicated proteins. d–f, 293T cells were transfected with the indicated plasmids (Flag-tagged GSDMA, Myc-tagged bacterial proteases) before analysed by phase-contrast microscopy (d), LDH release (e) and immunoblot of whole cell lysates with the indicated antibodies (f). g, h, Flag-tagged GSDMA was treated or not with SpeB, staphopains (ScpA, SspB), or cathepsins (Cathepsin B, L, D) before subjected to immunoblot analysis with the indicated antibodies. i, GSDMA N-terminal and C-terminal cleavage products (p27 and p23) were analysed by mass spectrometry (MS) and Edman sequencing, respectively. Individual peptides identified by MS and shown in black bars were mapped against N-terminal GSDMA (upper right panel). Middle right panel shows the N-terminal sequence of p23 determined by Edman sequencing, the diagram of GSDMA two-domain architecture, and SpeB cleavage site Gln246 highlighted in green. Bottom panel shows the positions (P) on the substrate of SpeB (GSDMA) which are counted and numbered (P3-P2-P1-P1’-P2’-P3’) from the point of cleavage. j, Whole cell lysates of 293T cells transfected with the indicated plasmids were collected and subjected to immunoblot analysis. Scale bar: 10 μm. Data are representative of at least three independent experiments. Graphs show mean ± s.d. of triplicate wells. e, One-way ANOVA. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 6 GSDMA-NT produced by SpeB cleavage is sufficient to initiate pyroptosis, but does not injure bystander cells.
a, Coomassie Blue-stained SDS-PAGE gel showing purified recombinant GSDMA, GSDMA-NT and GSDMA-CT. b–d, Equal amounts of recombinant full-length GSDMA, GSDMA-NT (1–246aa), GSDMA-CT, full-length GSDMD, Caspase-11 or full-length GSDMD plus Caspase-11 were electroporated into 293T cells respectively, followed by cell morphology observation by phase-contrast microscopy (b), cell viability analysis by CellTiter-Glo luminescent assay (c), and cell death assessment by PI uptake (d). e–g, Equal amounts of recombinant of full-length GSDMA, GSDMA-NT (1–246aa), GSDMA-CT, full-length GSDMD, Caspase-11 or full-length GSDMD plus Caspase-11 were respectively added directly into cell culture medium, followed by cell morphology observation by phase-contrast microscopy (e), cell viability analysis by CellTiter-Glo luminescent assay (f), and cell death assessment by PI uptake (g). Pyroptotic cells form large ballooning bubbles; Scale bar: 20 μm. Graphs show mean ± s.d. of triplicate wells (c, f) or mean ± s.e.m. of quadruplicate wells (d, g). c, Two-tailed Student’s t-test. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 7 GSDMA 1-246aa, but not 1-214aa possesses pyroptosis-inducing activity.
a, Coomassie Blue-stained SDS-PAGE gel showing recombinant engineered GSDMA with Flag tag-3C protease cleavage sequence inserted immediately after residue G214, Q246, treated with 3C protease. b–d, 293T cells were transfected with the indicated plasmids (Empty vector or Flag-tagged Gasdermin) before cell death was observed by phase-contrast microscopy (b) and determined by LDH release assay (c), whole cell lysates were collected for immunoblot analysis (d). Arrowheads indicate pyroptotic cells; Scale bar: 10 μm. Graphs show mean ± s.d. of triplicate wells. c, Two-tailed Student’s t-test. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 8 Phospholipid binding property and liposome-disrupting activity of GSDMA-NT.
a, Lipid strips dotted with indicated phospholipids (left panel) were incubated with noncovalent complex of cleaved GSDMA with a Flag-tag inserted right before the cleavage site, unprocessed full-length GSDMA, or 3C protease, followed by immunoblot analysis with an anti-Flag antibody (right panel). b, Indicated liposomes incubated with noncovalent complex of cleaved GSDMA (NT + CT) and full-length GSDMA (FL) were subjected to sedimentation by ultracentrifugation. Proteins in both liposome-free supernatant (S) and liposome-containing pellet (P) were analysed by SDS-PAGE. c, Indicated recombinant proteins incubated or not with CL liposomes and glutaraldehyde were analyzed by SDS-agarose gel electrophoresis and subsequent Coomassie Blue staining. d–h, Leakage of PC-PE liposomes containing additional PS or CL was monitored in real-time by terbium (Tb3+) fluorescence after incubation with recombinant gasdermins proteins in the presence or absence of recombinant SpeB or enzymatically inactive SpeB C192S (mSpeB) as indicated, or cysteine protease inhibitor E64 if necessary. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 9 GSDMA proteins in different species.
Multiple sequences alignment of human (h), chimpanzee (cp), monkey (mk), rat (r), dog (dg) GSDMA and mouse Gsdma1, Gsdma2 and Gsdma3 was performed using the ClustalW2 algorithm and plotted by ESPript program. Identical residues are highlighted by red background, and similar residues are indicated in red. Ile 245 and Gln246 (*) in human GSDMA are highly conserved in chimpanzee, monkey, rat, dog GSDMA as well as mouse Gsdma1.
Extended Data Fig. 10 SpeB cleaves mouse Gsdma1 and releases its N-terminal pyroptosis-inducing activity.
a, Whole cell lysates of 293T cells transfected with the indicated plasmids were collected and subjected to immunoblot analysis with the indicated antibodies. b, Coomassie Blue-stained SDS-PAGE gel showing in vitro cleavage of recombinant WT Gsdma1 or mutant Gsdma1 I246N/Q247E (1 μM) incubated with or without recombinant WT SpeB (100 nM) for 0.5 h. c, Whole cell lysates of 293T cells transfected with the indicated plasmids were collected and subjected to immunoblot analysis. d, Leakage of PC-PE liposomes containing additional PS or CL was monitored in real-time by terbium (Tb3+) fluorescence after incubation with recombinant gasdermins proteins in the presence or absence of recombinant SpeB as indicated. e, f, 293T cells transfected with the indicated plasmids were analysed by phase-contrast microscopy (e), LDH release (f). Arrowheads indicate pyroptotic cells; Scale bar: 10 μm. Graphs show mean ± s.d. of triplicate wells. f, One-way ANOVA. Data are representative of at least three independent experiments. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 11 Gsdma1 deficiency affects host immune responses against subcutaneous but not intraperitoneal infection of GAS WT.
a, WT and Gsdma1−/− mice were subcutaneously infected or not with GAS isolate M1T1 strain 5448 or its isogenic mutant strain (ΔspeB variant). IHC analysis of neutrophil infiltration at infection site on day 1. Scale bar: 100 μm. b, Quantification of neutrophil infiltration at infection site. c, Cutaneous sections from Gsdma1-/- mice infected or not for 18 h with FITC-labelled GAS WT were subjected to immunofluorescence staining with anti-keratin 14. Nucleus was stained with DAPI. Dashed lines delineate the boundaries of epidermis. Scale bar: 10 μm. d, Survival rate of mice intraperitoneally administrated with the indicated GAS (n = 12 mice per group). e, Model of SpeB-triggered GSDMA activation and subsequent pyroptosis of skin epithelial cells during GAS infection. b, show mean ± s.d. (n = 5 mice per group); Two-tailed Student’s t-test. Data are representative of at least three independent experiments.
Supplementary information
Supplementary Figure 1
Uncropped blots used to prepare main and extended data figures.
Supplementary Table 1
Oligonucleotide primers used in this study for cloning DNA fragments containing cepA, mac, covR/S, speB, emm, Rgg and RocA genes from the GAS genome.
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Deng, W., Bai, Y., Deng, F. et al. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis. Nature 602, 496–502 (2022). https://doi.org/10.1038/s41586-021-04384-4
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DOI: https://doi.org/10.1038/s41586-021-04384-4
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