Defective immuno- and thymoproteasome assembly causes severe immunodeficiency.

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

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie

UniBE Contributor:

McCoy, Kathleen and Macpherson, Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2045-2322

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Thi Thao Anh Pham

Date Deposited:

23 Jan 2019 17:53

Last Modified:

27 Jan 2019 02:35

Publisher DOI:

10.1038/s41598-018-24199-0

PubMed ID:

29654304

BORIS DOI:

10.7892/boris.122385

URI:

https://boris.unibe.ch/id/eprint/122385

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