Defective immuno- and thymoproteasome assembly causes severe immunodeficiency

• Published in: Scientific reports Vol. 8; no. 1; pp. 5975 - 18
• Main Authors: Treise, Irina, Huber, Eva M., Klein-Rodewald, Tanja, Heinemeyer, Wolfgang, Grassmann, Simon A., Basler, Michael, Adler, Thure, Rathkolb, Birgit, Helming, Laura, Andres, Christian, Klaften, Matthias, Landbrecht, Christina, Wieland, Thomas, Strom, Tim M., McCoy, Kathy D., Macpherson, Andrew J., Wolf, Eckhard, Groettrup, Marcus, Ollert, Markus, Neff, Frauke, Gailus-Durner, Valerie, Fuchs, Helmut, Hrabě de Angelis, Martin, Groll, Michael, Busch, Dirk H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.04.2018; Nature Publishing Group
• Subjects: 14/63; 45/23; 45/47; 631/250/1933; 631/250/249/2512; 631/337/474/2085; 631/80/304; 631/80/474/2085; 64/60; 82/51; 82/83; 96/21; Amino acids; Cell survival; Endopeptidases; Ethyl nitrosourea; Evolution; Heterozygotes; Homozygotes; Humanities and Social Sciences; Immunopathogenesis; Lymphocytes T; multidisciplinary; Mutagenesis; Mutation; Phenotypes; Point mutation; Proteasomes; Science; Science (multidisciplinary); Severe combined immunodeficiency; Yeast
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-24199-0

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.