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Sci Rep. 2018 Apr 13;8(1):5975. doi: 10.1038/s41598-018-24199-0.

Defective immuno- and thymoproteasome assembly causes severe immunodeficiency.

Author information

1
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstr. 30, 81675, Munich, Germany.
2
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
3
German Center for Infection Research (DZIF), Trogerstr. 30, 81675, Munich, Germany.
4
Center for Integrated Protein Science at the Department Chemistry, Chair of Biochemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, Germany.
5
Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
6
Division of Immunology, Department of Biology, University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
7
Institute for Molecular Animal Breeding and Biotechnology, Gene Center of the Ludwig-Maximilians-Universität München, Feodor-Lynen Str. 25, 81377, Munich, Germany.
8
German Center for Diabetes Research (DZD), Ingostädter Landstr. 1, 85764, Neuherberg, Germany.
9
Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Str. 29, 80802, Munich, Germany.
10
Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
11
Institute of Human Genetics, Technical University of Munich, 81675, Munich, Germany.
12
University Clinic of Visceral Surgery and Medicine, Departement Klinische Forschung, University of Bern, Murtenstr. 35, CH-3010, Bern, Switzerland.
13
Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg.
14
Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, DK-5000, Odense C, Denmark.
15
Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technical University of Munich, 85354, Freising, Weihenstephan, Germany.
16
Center for Integrated Protein Science at the Department Chemistry, Chair of Biochemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, Germany. michael.groll@tum.de.
17
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstr. 30, 81675, Munich, Germany. dirk.busch@tum.de.
18
Focus Group "Clinical Cell Processing and Purification", Institute for Advanced Study, Technical University of Munich, 81675, Munich, Germany. dirk.busch@tum.de.
19
German Center for Infection Research (DZIF), Trogerstr. 30, 81675, Munich, Germany. dirk.busch@tum.de.

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.

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