NOD mice are defective in proteasome production and activation of NF-kappaB.
The nonobese diabetic (NOD) mouse is an animal model of human type I diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) of the genome. We have identified in NOD lymphocytes a specific proteasome defect that results from the lack of the LMP2 subunit. The pronounced proteasome defect results in defective production and activation of the transcription factor NF-kappaB, which plays an important role in immune and inflammatory responses as well as in preventing apoptosis induced by tumor necrosis factor alpha. The defect in proteasome function in NOD mouse splenocytes was evident from impaired NF-kappaB subunit p50 and p52 generation by proteolytic processing and impaired degradation of the NF-kappaB-inhibitory protein IkappaBalpha. An obligatory role of MHC-linked proteasome subunits in transcription factor processing and activation has been established in a spontaneous-disease model and mutant cells similarly lacking the MHC-encoded subunit. These data suggest that NOD proteasome dysfunction is due to a tissue- and developmental-stage-specific defect in expression of the MHC-linked Lmp2 gene, resulting in altered transcription factor NF-kappaB activity, and that this defect contributes to pathogenesis in NOD mice. These observations are consistent with the diverse symptomatology of type I diabetes and demonstrate clear sex-, tissue-, and age-specific differences in the expression of this error which parallel the initiation and disease course of insulin-dependent (type I) diabetes mellitus.
Hayashi
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Immunobiology Laboratory, Massachusetts General Hospital-East, and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Faustman
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D
D000818:Animals; D017209:Apoptosis; D002457:Cell Extracts; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D017353:Gene Deletion; D008214:Lymphocytes / Q000378:metabolism; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D009097:Multienzyme Complexes / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002457:Cell Extracts; D009097:Multienzyme Complexes; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex