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Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

Nature Immunology volume 21, pages 857–867 (2020)Cite this article

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Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

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Fig. 1: Turkish population haplotypes provide evidence of evolutionarily recent positive selection of FMF-associated pyrin mutations.
Fig. 2: The pyrin inflammasome is suppressed by Y. pestis YopM through phosphorylation and subsequent 14-3-3 binding.
Fig. 3: YopM recruits host RSK to phosphorylate pyrin and suppress inflammasome activation.
Fig. 4: YopM interacts with pyrin and RSK.
Fig. 5: YopM binding to and phosphorylation of FMF mutant human pyrin is substantially reduced relative to WT human pyrin.
Fig. 6: FMF mutations are associated with increased Y. pestis-induced IL-1β release from human myeloid cell lines and PBMCs.
Fig. 7: The human C-terminal pyrin B30.2 domain regulates pyrin inflammasome activation.
Fig. 8: FMF mutations confer an IL-1β-dependent survival advantage against Y. pestis infection in mice.

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Data availability

The datasets generated and/or analyzed during the current study are available from the Supplementary Information and Source Data files in the online version of the paper and also available from the corresponding author on request.

Code availability

Computer code for the forward-time simulations is available at https://github.com/dshriner/forward-time-simulators under the GNU General Public License v.3.0.

References

  1. International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).

    Google Scholar 

  2. French_FMF_Consortium. A candidate gene for familial Mediterranean fever. Nat. Genet. 17, 25–31 (1997).

    Google Scholar 

  3. Chae, J. J. et al. Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity 34, 755–768 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Sohar, E., Gafni, J., Pras, M. & Heller, H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am. J. Med. 43, 227–253 (1967).

    PubMed  CAS  Google Scholar 

  5. Touitou, I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur. J. of Hum. Genet. 9, 473–483 (2001).

    CAS  Google Scholar 

  6. Kirino, Y. et al. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the Toll-like receptor 4 gene TLR4 in Behçet disease. Proc. Natl Acad. Sci. USA 110, 8134–8139 (2013).

    PubMed  CAS  Google Scholar 

  7. Papadopoulos, V. P., Giaglis, S., Mitroulis, I. & Ritis, K. The population genetics of familial Mediterranean fever: a meta-analysis study. Ann. Hum. Genet. 72, 752–761 (2008).

    PubMed  CAS  Google Scholar 

  8. Yilmaz, E. et al. Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population. Eur. J. Hum. Genet. 9, 553–555 (2001).

    PubMed  CAS  Google Scholar 

  9. Koshy, R., Sivadas, A. & Scaria, V. Genetic epidemiology of familial Mediterranean fever through integrative analysis of whole genome and exome sequences from Middle East and North Africa. Clin. Genet. 93, 92–102 (2018).

    PubMed  CAS  Google Scholar 

  10. Zvereff, V. V., Faruki, H., Edwards, M. & Friedman, K. J. Cystic fibrosis carrier screening in a North American population. Genet. Med. 16, 539–546 (2014).

    PubMed  CAS  Google Scholar 

  11. Xu, H. et al. Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature 513, 237–241 (2014).

    PubMed  CAS  Google Scholar 

  12. Park, Y. H., Wood, G., Kastner, D. L. & Chae, J. J. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat. Immunol. 17, 914–921 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Chung, L. K. et al. The Yersinia virulence factor YopM hijacks host kinases to inhibit type III effector-triggered activation of the pyrin inflammasome. Cell Host Microbe 20, 296–306 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Ratner, D. et al. The Yersinia pestis effector YopM inhibits pyrin inflammasome activation. PLoS Pathog. 12, e1006035 (2016).

    PubMed  PubMed Central  Google Scholar 

  15. Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).

    PubMed  PubMed Central  Google Scholar 

  16. Ferrer-Admetlla, A., Liang, M., Korneliussen, T. & Nielsen, R. On detecting incomplete soft or hard selective sweeps using haplotype structure. Mol. Biol. Evol. 31, 1275–1291 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Gandolfo, L. C., Bahlo, M. & Speed, T. P. Dating rare mutations from small samples with dense marker data. Genetics 197, 1315–1327 (2014).

    PubMed  PubMed Central  Google Scholar 

  18. Moorjani, P. et al. A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years. Proc. Natl Acad. Sci. USA 113, 5652–5657 (2016).

    PubMed  CAS  Google Scholar 

  19. Chen, H., Hey, J. & Slatkin, M. A hidden Markov model for investigating recent positive selection through haplotype structure. Theor. Popul. Biol. 99, 18–30 (2015).

    PubMed  Google Scholar 

  20. Hashemi Shahraki, A., Carniel, E. & Mostafavi, E. Plague in Iran: its history and current status. Epidemiol. Health 38, e2016033 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. McDonald, C., Vacratsis, P. O., Bliska, J. B. & Dixon, J. E. The Yersinia virulence factor YopM forms a novel protein complex with two cellular kinases. J. Biol. Chem. 278, 18514–18523 (2003).

    PubMed  CAS  Google Scholar 

  22. Hentschke, M. et al. Yersinia virulence factor YopM induces sustained RSK activation by interfering with dephosphorylation. PLoS ONE 5, e13165 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. Evdokimov, A. G., Anderson, D. E., Routzahn, K. M. & Waugh, D. S. Unusual molecular architecture of the Yersinia pestis cytotoxin YopM: a leucine-rich repeat protein with the shortest repeating unit. J. Mol. Biol. 312, 807–821 (2001).

    PubMed  CAS  Google Scholar 

  24. McPhee, J. B., Mena, P. & Bliska, J. B. Delineation of regions of the Yersinia YopM protein required for interaction with the RSK1 and PRK2 host kinases and their requirement for interleukin-10 production and virulence. Infect. Immun. 78, 3529–3539 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  25. McCoy, M. W., Marre, M. L., Lesser, C. F. & Mecsas, J. The C-terminal tail of Yersinia pseudotuberculosis YopM is critical for interacting with RSK1 and for virulence. Infect. Immun. 78, 2584–2598 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Aubert, D. F. et al. A Burkholderia type VI effector deamidates Rho GTPases to activate the pyrin inflammasome and trigger inflammation. Cell Host Microbe 19, 664–674 (2016).

    PubMed  CAS  Google Scholar 

  27. Allison, A. C. Protection afforded by sickle-cell trait against subtertian malarial infection. Br. Med. J. 1, 290–294 (1954).

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Chae, J. J. et al. Isolation, genomic organization, and expression analysis of the mouse and rat homologs of MEFV, the gene for familial Mediterranean fever. Mamm. Genome 11, 428–435 (2000).

    PubMed  CAS  Google Scholar 

  29. Osei-Owusu, P., Charlton, T. M., Kim, H. K., Missiakas, D. & Schneewind, O. FPR1 is the plague receptor on host immune cells. Nature 574, 57–62 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Achtman, M. et al. Yersinia pestis, the cause of plague, is a recently emerged clone of Yersinia pseudotuberculosis. Proc. Natl Acad. Sci. USA 96, 14043–14048 (1999).

    PubMed  CAS  Google Scholar 

  31. Wagner, D. M. et al. Yersinia pestis and the plague of Justinian 541–543 AD: a genomic analysis. Lancet Infect. Dis. 14, 319–326 (2014).

    PubMed  Google Scholar 

  32. Achtman, M. How old are bacterial pathogens? Proc. Biol. Sci. 283, 20160990 (2016).

    PubMed  PubMed Central  Google Scholar 

  33. Kogan, A. et al. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am. J. Med. Genet. 102, 272–276 (2001).

    PubMed  CAS  Google Scholar 

  34. Ben-Chetrit, E. & Touitou, I. Familial Mediterranean fever in the world. Arthritis Rheum. 61, 1447–1453 (2009).

    PubMed  CAS  Google Scholar 

  35. Ben-Chetrit, E. & Levy, M. Familial Mediterranean fever. Lancet 351, 659–664 (1998).

    PubMed  CAS  Google Scholar 

  36. Zhao, Y. & Shao, F. Diverse mechanisms for inflammasome sensing of cytosolic bacteria and bacterial virulence. Curr. Opin. Microbiol. 29, 37–42 (2016).

    PubMed  Google Scholar 

  37. Remmers, E. F. et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease. Nat. Genet. 42, 698–702 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    PubMed  CAS  Google Scholar 

  39. Loh, P. R., Palamara, P. F. & Price, A. L. Fast and accurate long-range phasing in a UK Biobank cohort. Nat. Genet. 48, 811–816 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  40. Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).

    PubMed  CAS  Google Scholar 

  41. Szpiech, Z. A. & Hernandez, R. D. selscan: an efficient multithreaded program to perform EHH-based scans for positive selection. Mol. Biol. Evol. 31, 2824–2827 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Mallick, S. et al. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature 538, 201–206 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  43. The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  44. Chae, J. J. et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol. Cell 11, 591–604 (2003).

    PubMed  CAS  Google Scholar 

  45. Chae, J. J. et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production. Proc. Natl Acad. Sci. USA 103, 9982–9987 (2006).

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients enrolled in our clinical protocols for providing research specimens, A. Jones, T. Romeo, L. Poe and R. Laird for help with caring for patients and A. Schaffer for thoughtful discussions. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Center for Research on Genomics and Global Health. This research was also supported by the National Institute of Allergy and Infectious Diseases award R01AI099222 (to J.B.B.) and utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Author information

Author notes

  1. Yong Hwan Park

    Present address: Center for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea

  2. Nicole A. Loeven & James B. Bliska

    Present address: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

  3. These authors contributed equally: Yong Hwan Park, Elaine F. Remmers.

Authors and Affiliations

  1. Inflammatory Disease Section, Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, Bethesda, MD, USA

    Yong Hwan Park, Elaine F. Remmers, Wonyong Lee, Amanda K. Ombrello, Deborah L. Stone, Patrycja Hoffmann, Michele Nehrebecky, Ivona Aksentijevich, Daniel L. Kastner & Jae Jin Chae

  2. Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Lawton K. Chung, Maya I. Ivanov, Nicole A. Loeven & James B. Bliska

  3. Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China

    Zhao Shilei & Hua Chen

  4. University of Chinese Academy of Sciences, Beijing, China

    Zhao Shilei & Hua Chen

  5. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China

    Zhao Shilei & Hua Chen

  6. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA

    Karyl S. Barron

  7. Department of Medical Biology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Yeliz Z. Akkaya-Ulum & Banu Balci-Peynircioglu

  8. Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Erdal Sag & Seza Ozen

  9. Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Ahmet Gül

  10. Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, USA

    Charles N. Rotimi & Daniel Shriner

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Contributions

J.J.C. conceived the project. Y.H.P., E.F.R., J.B.B., D.L.K. D.S. and J.J.C. designed the study. Y.H.P., E.F.R., W.L., L.K.C., M.I.I., N.A.L., Y.Z.A.-U., B.B.-P., D.S. and J.J.C. performed experiments. Y.H.P., E.F.R., W.L., Z.S., I.A., C.N.R., H.C., J.B.B., D.L.K., D.S. and J.J.C. analyzed the data. Y.H.P., E.F.R., I.A., C.N.R., J.B.B., D.L.K., D.S. and J.J.C. wrote the manuscript. A.K.O., D.L.S., K.S.B., P.H., M.N., E.S., I.A., A.G. and S.O. provided the clinical data and specimens for healthy controls, carriers and patients. B.B.-P. and S.Z. provided laboratory resources and assistance at the Hacettepe University Faculty of Medicine.

Corresponding authors

Correspondence to Daniel L. Kastner or Jae Jin Chae.

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Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Haplotypes from 2,313 Turkish individuals provide evidence of evolutionarily recent positive selection and estimates of selection intensity and duration of selection on FMF-associated pyrin mutations.

a-c, Histograms of unstandardized nSL statistics of GWAS variants37 with similar frequency and local recombination rate as each FMF mutation. a, 1,402 markers similar to MEFV_p.V726A; b, 2,380 markers similar to MEFV_p.M694V; and c, 5,442 markers similar to MEFV_p.E148Q. The most extreme negative nSL values have the strongest evidence of recent positive selection. d-f, Log-likelihood plots and selection co-efficient estimates with 95% confidence intervals and mutation age estimates with 95% confidence intervals of three MEFV mutations, determined with a hidden Markov model method from the multi-locus haplotype structure of 4,626 Turkish chromosomes. d, MEFV_p.V726A; e, MEFV_p.M694V; and f, MEFV_p.E148Q. g-i, Histograms of iHH values for the ancestral alleles of markers with similar allele frequency and local recombination rate as each MEFV mutation, demonstrating that the ancestral alleles have not been under positive selection, thereby providing evidence that the mutations have not been under balancing selection. g, 1,570 markers similar to MEFV_ p.V726, h, 2,677 markers similar to MEFV_p.M694, and i, 6,166 markers similar to MEFV_p.E148.

Source data

Extended Data Fig. 2 Geographically diverse FMF mutation carriers exhibit extended conserved haplotypes.

a, MEFV_p.M694V conserved haplotypes (yellow). The length of the MEFV_p.M694V haplotype shared by all the diverse carrier chromosomes = 48 kb and shared by greater than 50% of the diverse carrier chromosomes = 307 kb. b, MEFV_p.V726A conserved haplotypes (pink). The length of the MEFV_p.V726A haplotype shared by all the diverse carrier chromosomes = 77 kb and shared by greater than 50% of the diverse carrier chromosomes = 262 kb. The fully conserved shared haplotypes in the diverse mutation carriers are identical to the respective haplotypes in the Turkish population.

Extended Data Fig. 3 Y. pestis YopM suppresses the pyrin inflammasome.

a,b, IL-1β measurements of culture supernatants of Mefv+/+ BMDMs primed with LPS, treated with or without C3 toxin, and infected with indicated MOI of WT (a) or ∆yopM (b) Y. pestis strains. Results are presented as mean ± s.e.m., for n = 5 independent biological replicates. c, Immunoblot analysis of pyrin and pro-IL-1β in lysates of retroviral transduced U937 cells, expressing WT or indicated Ser to Ala mutant pyrin proteins. Data are representative of three independent experiments with similar results.

Source data

Extended Data Fig. 4 RSK-YopM mediated pyrin phosphorylation is independent of PKN.

In vitro kinase assay of purified Myc/His-tagged N-terminal human pyrin (amino acids 1–330) incubated with recombinant PKN1 and/or RSK1 (a) or PKN2 and/or RSK1 (b) in the presence of purified GST or GST-YopM, and analyzed by immunoblot with antibody specific for S242 phosphorylated pyrin (a) or phosphorylated serine (b). Data are representative of three independent experiments with similar results.

Source data

Extended Data Fig. 5 5 Human and murine RSK isoforms exhibit a restricted distribution of gene expression in leukocytes.

a,b, Relative gene expression profile of RSK isoforms in human PBMCs with or without Y. pestis infection (a) and mouse BMDMs with or without LPS priming (b), and assayed by RT-QPCR. Results are presented as mean ± s.e.m., for n = 5 independent biological replicates.

Source data

Extended Data Fig. 6 Knockdown of RSK1, RSK2 and RSK3 in THP-1 cells induces ASC oligomerization.

a, Immunoblot analysis of lysates of THP-1 cells transiently transfected with negative control siRNA with no substantial sequence similarity to human gene sequences (N.C.) or a mixture of siRNAs targeting RSK1, RSK2 and RSK3. b, ASC oligomerization analysis by immunoblot from THP-1 cells transfected with N.C. or a mixture of siRNAs targeting RSK1, RSK2 and RSK3, and infected with Y. pestis (MOI 30). Cell lysates and the disuccinimidyl suberate (DSS)-treated pellets were analyzed by immunoblot with anti-ASC antibody. Data are representative of three independent experiments with similar results.

Source data

Extended Data Fig. 7 YopM binds to multiple regions of N-terminal pyrin.

a, Schematic structure of human pyrin with various deletion fragments of N-terminal human pyrin. b,c, GST-pulldown assay of V5-tagged various N-terminal human pyrin fragments with purified GST-YopM. Data are representative of three independent experiments with similar results.

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Park, Y.H., Remmers, E.F., Lee, W. et al. Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis. Nat Immunol 21, 857–867 (2020). https://doi.org/10.1038/s41590-020-0705-6

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