1. Defective immuno- and thymoproteasome assembly causes severe immunodeficiency
- Author
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Thomas Wieland, Tim M. Strom, Kathy D. McCoy, Christian Andres, Eckhard Wolf, Birgit Rathkolb, Eva M. Huber, Simon Grassmann, Christina Landbrecht, Laura Helming, Valerie Gailus-Durner, Frauke Neff, Thure Adler, Michael Basler, Marcus Groettrup, Andrew J. Macpherson, Irina Treise, Martin Hrabě de Angelis, Wolfgang Heinemeyer, Markus Ollert, Michael Groll, Tanja Klein-Rodewald, Matthias Klaften, Helmut Fuchs, and Dirk H. Busch
- Subjects
Male ,0301 basic medicine ,Proteasome Endopeptidase Complex ,Cell Survival ,Mutant ,lcsh:Medicine ,Mutagenesis (molecular biology technique) ,610 Medicine & health ,Mice, SCID ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,ddc:570 ,medicine ,Animals ,Humans ,Missense mutation ,lcsh:Science ,Immunodeficiency ,Mice, Knockout ,Mice, Inbred BALB C ,Severe combined immunodeficiency ,Multidisciplinary ,Point mutation ,lcsh:R ,medicine.disease ,Molecular biology ,ddc ,3. Good health ,Mice, Inbred C57BL ,Protein Subunits ,030104 developmental biology ,Proteasome assembly ,Knockout mouse ,lcsh:Q ,Female ,Cell death and immune response, Mechanisms of disease, Primary immunodeficiency disorders, Proteasome ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2018