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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; Gröttrup, Marcus; Ollert, Markus; Neff, Frauke; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabe de Angelis, Martin; Groll, Michael; Busch, Dirk H. (2018): Defective immuno- and thymoproteasome assembly causes severe immunodeficiency. In: Scientific Reports, Vol. 8, 5975
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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 beta 2i-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 beta 2i 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 beta 1i (LMP2) and beta 5i (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.