Defective immuno- and thymoproteasome assembly causes severe immunodeficiency.

April 13, 2018 By:
  • Treise I
  • Huber EM
  • Klein-Rodewald T
  • Heinemeyer W
  • Grassmann SA
  • Basler M
  • Adler T
  • Rathkolb B
  • Helming L
  • Andres C
  • Klaften M
  • Landbrecht C
  • Wieland T
  • Strom TM
  • McCoy KD
  • Macpherson AJ
  • Wolf E
  • Groettrup M
  • Ollert M
  • Neff F
  • Gailus-Durner V
  • Fuchs H
  • Hrabe de Angelis M
  • Groll M
  • Busch DH.

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 beta2i-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 beta2i 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 beta1i (LMP2) and beta5i (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.

2018 Apr. Sci Rep.8(1):5975.
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