Letter | Published:

The autoimmune disease–associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness

Nature Genetics volume 43, pages 902907 (2011) | Download Citation

Abstract

A variant of the PTPN22-encoded Lyp phosphatase (Lyp620W) confers risk for autoimmune disease, but the mechanisms underlying this association remain unclear. We show here that mice expressing the Lyp variant homolog Pep619W manifest thymic and splenic enlargement accompanied by increases in T-cell number, activation and positive selection and in dendritic- and B-cell activation. Although Ptpn22 (Pep) transcript levels were comparable in Pep619W and wild-type Pep619R mice, Pep protein levels were dramatically reduced in the mutant mice, with Pep619W protein being more rapidly degraded and showing greater association with and in vitro cleavage by calpain 1 than Pep619R. Similarly, levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wild-type Lyp620R. Thus, calpain-mediated degradation with consequently reduced Lyp/Pep expression and lymphocyte and dendritic cell hyperresponsiveness represents a mechanism whereby Lyp620W may increase risk for autoimmune disease.

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Acknowledgements

The authors acknowledge the assistance of K. Carrington (Mount Sinai Hospital) and M. Keogh (The Feinstein Institute for Medical Research) in recruiting subjects for these studies, H. Yao and G. Jiang for their technical assistance, D. Davidson and A. Veillette (Institute de Recherches Cliniques de Montreal) for their generosity in providing Pep-specific antibody, and A. Goldman in manuscript preparation and review. This work was supported by grants from the Canadian Institute for Health Research (MOP10730 and MOP79321), the Canadian Arthritis Network (07-SRID-IJD-03) and the Ontario Research Fund (RE01-061). K.A.S. is supported by a Canada Research Chair and holds the Sherman Family Chair in Genomic Medicine.

Author information

Affiliations

  1. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Jinyi Zhang
    • , Naima Zahir
    • , Qiuhong Jiang
    • , Helen Miliotis
    • , Stephanie Heyraud
    • , Xianwang Meng
    • , Baoxia Dong
    • , Gang Xie
    • , Frank Qiu
    • , Edward C Keystone
    •  & Katherine A Siminovitch
  2. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

    • Jinyi Zhang
    • , Naima Zahir
    • , Qiuhong Jiang
    • , Helen Miliotis
    • , Stephanie Heyraud
    • , Xianwang Meng
    • , Baoxia Dong
    • , Gang Xie
    • , Frank Qiu
    •  & Katherine A Siminovitch
  3. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Jinyi Zhang
    • , Naima Zahir
    • , Qiuhong Jiang
    • , Helen Miliotis
    • , Stephanie Heyraud
    • , Xianwang Meng
    • , Baoxia Dong
    • , Gang Xie
    • , Frank Qiu
    •  & Katherine A Siminovitch
  4. Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.

    • Jinyi Zhang
    • , Naima Zahir
    • , Qiuhong Jiang
    • , Helen Miliotis
    • , Stephanie Heyraud
    • , Xianwang Meng
    • , Baoxia Dong
    • , Gang Xie
    • , Frank Qiu
    •  & Katherine A Siminovitch
  5. Toronto General Research Institute, Toronto, Ontario, Canada.

    • Jinyi Zhang
    • , Naima Zahir
    • , Qiuhong Jiang
    • , Helen Miliotis
    • , Stephanie Heyraud
    • , Xianwang Meng
    • , Baoxia Dong
    • , Gang Xie
    • , Frank Qiu
    •  & Katherine A Siminovitch
  6. Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.

    • Zhenyue Hao
  7. Canadian Institutes of Health Research Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada.

    • Christopher A McCulloch
  8. Laboratory of Developmental Biology, Royal Victoria Hospital, McGill University Health Center, McGill University, Montreal, Quebec, Canada.

    • Alan C Peterson

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Contributions

J.Z. and K.A.S. designed the study. N.Z. and B.D. performed most of the flow cytometry analyses. Q.J. and A.C.P. derived the knock-in mice. H.M. and S.H. carried out the calpain and ubiquitination analyses. X.M., G.X., F.Q. and Z.H. carried out and/or derived reagents for other protein and RNA analyses. E.C.K., J.Z. and K.A.S. obtained and/or analyzed the human samples. J.Z., C.A.M., E.C.K., A.C.P. and K.A.S. played key roles in data analysis and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Katherine A Siminovitch.

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DOI

https://doi.org/10.1038/ng.904

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