Defective immuno- and thymoproteasome assembly causes severe immunodeficiency
| Autor: | 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, Dirk H. Busch |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | 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 2018, ' Defective immuno-and thymoproteasome assembly causes severe immunodeficiency ', Scientific Reports, vol. 8, 5975 . https://doi.org/10.1038/s41598-018-24199-0 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, Kathleen; Macpherson, Andrew; Wolf, Eckhard; Groettrup, Marcus; Ollert, Markus; Neff, Frauke; ... (2018). Defective immuno-and thymoproteasome assembly causes severe immunodeficiency. Scientific Reports, 8(1), p. 5975. Nature Publishing Group 10.1038/s41598-018-24199-0 Sci. Rep. 8:5975 (2018) Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-18 (2018) |
| DOI: | 10.1038/s41598-018-24199-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|