A role for NF-kappaB and the proteasome in autoimmunity.
Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor alpha (TNF-alpha). The proteasome dysfunction is both tissue and developmental stage specific and likely contributes to disease pathogenesis and tissue targeting.
Hayashi
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T
Immunobiology Laboratory, Massachusetts General Hospital, and Harvard Medical School, Charlestown 02129, USA.
Faustman
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D
D000818:Animals; D015551:Autoimmunity; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics*; D013154:Spleen / Q000276:immunology
D009097:Multienzyme Complexes; D016328:NF-kappa B; D011506:Proteins; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex