Defective immuno- and thymoproteasome assembly causes severe immunodeficiency

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2018
Autor:innen
Treise, Irina
Huber, Eva M.
Klein-Rodewald, Tanja
Heinemeyer, Wolfgang
Grassmann, Simon A.
Adler, Thure
Groll, Michael
Busch, Dirk H.
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Scientific reports. 2018, 8(1), 5975. eISSN 2045-2322. Available under: doi: 10.1038/s41598-018-24199-0
Zusammenfassung

By N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated the mutant mouse line TUB6 that is characterised by severe combined immunodeficiency (SCID) and systemic sterile autoinflammation in homozygotes, and a selective T cell defect in heterozygotes. The causative missense point mutation results in the single amino acid exchange G170W in multicatalytic endopeptidase complex subunit-1 (MECL-1), the β2i-subunit of the immuno- and thymoproteasome. Yeast mutagenesis and crystallographic data suggest that the severe TUB6-phenotype compared to the MECL-1 knockout mouse is caused by structural changes in the C-terminal appendage of β2i that prevent the biogenesis of immuno- and thymoproteasomes. Proteasomes are essential for cell survival, and defective proteasome assembly causes selective death of cells expressing the mutant MECL-1, leading to the severe immunological phenotype. In contrast to the immunosubunits β1i (LMP2) and β5i (LMP7), mutations in the gene encoding MECL-1 have not yet been assigned to human disorders. The TUB6 mutant mouse line exemplifies the involvement of MECL-1 in immunopathogenesis and provides the first mouse model for primary immuno- and thymoproteasome-associated immunodeficiency that may also be relevant in humans.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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Cell death and immune response, Mechanisms of disease, Primary immunodeficiency disorders, Proteasome
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ISO 690TREISE, Irina, Eva M. HUBER, Tanja KLEIN-RODEWALD, Wolfgang HEINEMEYER, Simon A. GRASSMANN, Michael BASLER, Thure ADLER, Marcus GRÖTTRUP, Michael GROLL, Dirk H. BUSCH, 2018. Defective immuno- and thymoproteasome assembly causes severe immunodeficiency. In: Scientific reports. 2018, 8(1), 5975. eISSN 2045-2322. Available under: doi: 10.1038/s41598-018-24199-0
BibTex
@article{Treise2018-04-13Defec-42174,
  year={2018},
  doi={10.1038/s41598-018-24199-0},
  title={Defective immuno- and thymoproteasome assembly causes severe immunodeficiency},
  number={1},
  volume={8},
  journal={Scientific reports},
  author={Treise, Irina and Huber, Eva M. and Klein-Rodewald, Tanja and Heinemeyer, Wolfgang and Grassmann, Simon A. and Basler, Michael and Adler, Thure and Gröttrup, Marcus and Groll, Michael and Busch, Dirk H.},
  note={Article Number: 5975}
}
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