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Treise, I. ; Huber, E.M.* ; Klein-Rodewald, T. ; Heinemeyer, W.* ; Grassmann, S.A.* ; Basler, M.* ; Adler, T. ; Rathkolb, B. ; Helming, L.* ; Andres, C.* ; Klaften, M. ; Landbrecht, C.* ; Wieland, T. ; Strom, T.M. ; McCoy, K.D.* ; Macpherson, A.J.* ; Wolf, E.* ; Groettrup, M.* ; Ollert, M.* ; Neff, F. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Groll, M.* ; Busch, D.H.*

Defective immuno- and thymoproteasome assembly causes severe immunodeficiency.

Sci. Rep. 8:5975 (2018)

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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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