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Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Naturevolume 429, pages75–79 (2004)Cite this article

Abstract

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10)1,2. Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-β cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease3. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production inex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.

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Figure 1: Identification of a caspase-12 point mutation in individuals of African descent.
Figure 2: Differential responsiveness to LPS and conA ofex vivo whole blood from wild-type, T125C heterozygous and T125C homozygous individuals of African descent.
Figure 3: Human caspase-12 is not involved in ER-stress-mediated apoptosis.
Figure 4: Inhibition of NF-κB activity by human caspase-12.

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References

  1. Nicholson, D. W. Caspase structure, proteolytic substrates, and function during apoptotic cell death.Cell Death Differ.6, 1028–1042 (1999)

    Article CAS  Google Scholar 

  2. Lamkanfi, M., Declercq, W., Kalai, M., Saelens, X. & Vandenabeele, P. Alice in caspase land. A phylogenetic analysis of caspases from worm to man.Cell Death Differ.9, 358–361 (2002)

    Article CAS  Google Scholar 

  3. Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β.Nature403, 98–103 (2000)

    Article ADS CAS  Google Scholar 

  4. Fischer, H., Koenig, U., Eckhart, L. & Tschachler, E. Human caspase 12 has acquired deleterious mutations.Biochem. Biophys. Res. Commun.293, 722–726 (2002)

    Article CAS  Google Scholar 

  5. Chan, S. L., Culmsee, C., Haughey, N., Klapper, W. & Mattson, M. P. Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12.Neurobiol. Dis.11, 2–19 (2002)

    Article CAS  Google Scholar 

  6. Kouroku, Y. et al. Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation.Hum. Mol. Genet.11, 1505–1515 (2002)

    Article CAS  Google Scholar 

  7. Shibata, M. et al. Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice.Neuroscience118, 491–499 (2003)

    Article CAS  Google Scholar 

  8. Mouw, G. et al. Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat.NeuroReport14, 183–186 (2003)

    Article CAS  Google Scholar 

  9. Stehlik, C. et al. The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-κB and pro-caspase-1 regulation.Biochem. J.373, 101–113 (2003)

    Article CAS  Google Scholar 

  10. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β.Mol. Cell10, 417–426 (2002)

    Article CAS  Google Scholar 

  11. Srinivasula, S. M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.J. Biol. Chem.277, 21119–21122 (2002)

    Article CAS  Google Scholar 

  12. Grenier, J. M. et al. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-κB and caspase-1.FEBS Lett.530, 73–78 (2002)

    Article CAS  Google Scholar 

  13. Bouchier-Hayes, L. & Martin, S. J. CARD games in apoptosis and immunity.EMBO Rep.3, 616–621 (2002)

    Article CAS  Google Scholar 

  14. Hotchkiss, R. S. et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte.Nature Immunol.1, 496–501 (2000)

    Article CAS  Google Scholar 

  15. Hotchkiss, R. S. et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans.J. Immunol.166, 6952–6963 (2001)

    Article CAS  Google Scholar 

  16. Green, R. C. et al. Risk of dementia among white and African American relatives of patients with Alzheimer disease.J. Am. Med. Assoc.287, 329–336 (2002)

    Article  Google Scholar 

  17. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease.Neurology34, 939–944 (1984)

    Article CAS  Google Scholar 

  18. Freeman, B. D., Buchman, T. G., McGrath, S., Tabrizi, A. R. & Zehnbauer, B. A. Template-directed dye-terminator incorporation with fluorescence polarization detection for analysis of single nucleotide polymorphisms implicated in sepsis.J. Mol. Diagn.4, 209–215 (2002)

    Article CAS  Google Scholar 

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Acknowledgements

We thank S. Menard, B. Simpson and the Granby Zoo for non-invasive samples for primate sequencing, and the West Island and Côte Des Neiges Black Community Associations for coordinating blood donor clinics. M.S. is supported by a CIHR postdoctoral fellowship; T.G.B. is supported by a grant from the NIGMS; L.A.F. is supported in part by grants from the NIH.

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Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research, Montreal, H9H 3L1, Quebec, Canada

    Maya Saleh, John P. Vaillancourt, Sophie Roy & Donald W. Nicholson

  2. Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, British Columbia, V5Z 4H4, Vancouver, Canada

    Rona K. Graham & Michael R. Hayden

  3. Departments of Medicine (Genetics Program & Hematology/Oncology Section), Neurology and Genetics & Genomics, and Center for Human Genetics, Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health, Massachusetts, 02118, Boston, USA

    Matthew Huyck, Martin H. Steinberg, Vikki Nolan, Clinton T. Baldwin & Lindsay A. Farrer

  4. Hematology/Oncology Section), Neurology and Genetics & Genomics, and Center for Human Genetics, Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health,

    Matthew Huyck, Martin H. Steinberg, Vikki Nolan, Clinton T. Baldwin & Lindsay A. Farrer

  5. Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA

    Srinivasa M. Srinivasula & Emad S. Alnemri

  6. Department of Anesthesiology, Department of Surgery, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Richard S. Hotchkiss & Timothy G. Buchman

  7. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Barbara A. Zehnbauer

Authors
  1. Maya Saleh

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  2. John P. Vaillancourt

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  3. Rona K. Graham

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  4. Matthew Huyck

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  5. Srinivasa M. Srinivasula

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  7. Martin H. Steinberg

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  8. Vikki Nolan

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  9. Clinton T. Baldwin

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  10. Richard S. Hotchkiss

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  11. Timothy G. Buchman

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  12. Barbara A. Zehnbauer

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  13. Michael R. Hayden

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  14. Lindsay A. Farrer

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  15. Sophie Roy

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  16. Donald W. Nicholson

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Corresponding author

Correspondence toDonald W. Nicholson.

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Competing interests

I am Vice President of Merck Research Laboratories and several of the authors are also employees of Merck. Although it is unlikely that these individuals or the company would gain or lose financially through publication of this paper, it is a possibility. It is, however, highly unlikely.

Supplementary information

Supplementary Information

Supplementary methods and tables showing: 1) Subgroup breakdown of genotype and allele frequency of T125 and T125C in different ethnic backgrounds; 2) Codon 125 in humans and counterparts in non-human primates, rodents and representative human cell-lines. (DOC 81 kb)

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Saleh, M., Vaillancourt, J., Graham, R.et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.Nature429, 75–79 (2004). https://doi.org/10.1038/nature02451

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