Abstract
Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile- -onset diabetes) is usually caused by T cell-mediated autoimmunity, with a pre-diabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic β 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 κB (NF-κB), 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 α (TNF-α). The proteasome dysfunction is both tissue and developmental stagespecific and likely contributes to disease pathogenesis and tissue targeting.
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References
Akiyama K. Y., Yokota K. Y., Kagawa S., Shimbara N., Tamura T., Akioka H., Nothwang H. G., Noda C., Tanaka K. and Ichihara A. (1994): cDNA cloning and interferon γ down-regulation of proteasomal subunits X and Y. Science, 265, 1231–1234.
Aldrich C. J., Ljunggren H. G., Van Kaer L., Ashton-Rickardt P. G., Tonegawa S. and Forman J. (1994): Positive selection of self-and alloreactive CD8+ T cells in TAP-1 mutant mice. Proc. Natl. Acad. Sci. USA, 91, 6525–6528.
Atkinson M. A. and Leiter E. H. (1999): The NOD mouse model of type 1 diabetes: as good as it gets? Nat. Med., 5, 601–604.
Baeuerle P. A. and Baltimore D. (1996): NF-kappa B: ten years after. Cell, 87, 13–20.
Baldwin A. S. (1996): The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol., 12, 141–179.
Beg A. A. and Baltimore D. (1996): An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science, 274, 782–784.
Beg A. A., Sha W. C, Bronson R. T., Ghosh S. and Baltimore D. (1995): Embryonic lethality and liver degeneration in mice lacking the relA component of NF-kappa B. Nature, 376, 167–170.
Belich M. P., Glynne R. J., Senger G., Sheer D. and Trowsdale J. (1994): Proteasome components with reciprocal expression to that of the MHC-encoded LMP proteins. Curr. Biol., 4, 769–776.
Belich M. P., Salmeron A., Johnston L. H. and Ley S. C. (1999): TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 pl05. Nature, 397, 363–368.
Bohnline E., Lowenthal J. W., Siekevitz M., Franza B. R. and Greene W. C. (1988): The same inducible nuclear protein regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell, 53, 827–836.
Burkly L., Hession C., Ogata L., Reilly C., Marconi L. A., Olson D., Tizard R., Cate R. and Lo D. (1995): Expression of relB is required for the development of thymic medulla and dendritic cells. Nature, 373, 531–536.
Bushdid P. B., Brantley D. M., Yull F. E., Blaeuer G. L., Hoffman L. H., Niswander L. and Kerr L. D. (1998): Inhibition of NF-κB activity results in disruption of the apical ectodermal ringe and aberrant limb morphogenesis. Nature, 392, 615–618.
Caamano J. H., Rizzo C. A., Durham S. K., Barton D. S., Raventos-Suarez C, Snapper C. M. and Bravo R. (1998): Nuclear factor (NF)-kappa B2 (pl00/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J. Exp. Med., 187, 185–196.
Coux O. and Goldberg A. L. (1998): Enzymes catalyzing ubiquitination and proteolytic processing of the pl05 precursor of nuclear factor κBI. J. Biol. Chem., 273, 8820–8828.
Coux O., Tanaka K. and Goldberg A. L. (1996): Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem., 65, 801–847.
Crisa L., Mordes J. P. and Rossini A. A. (1992): Autoimmune diabetes mellitus in the BB rat. Diabetes Metab. Rev., 8, 9–37.
Cross S. L., Halden N. F., Lenardo M. and Leonard W. J. (1989): Functionally distinct NF-kappa B binding sites in the immunoglobulin kappa and IL-2 receptor alpha chain genes. Science, 244, 466–468.
Cui H., Matusi K., Omura S., Schaver S. L., Matulka R. A., Sonenshein G. E. and Ju S. T. (1997): Proteasome regulation of activation-induced T cell death. Proc. Natl. Acad. Sci. USA, 94,7515–7520.
Fan C. M. and Maniatis T. (1991): Generation of p50 subunit of NF-κB by processing of p105 through an ATP-dependent pathway. Nature, 354, 395–398.
Faustman D., Eisenbarth G. and Daley J. (1989): Abnormal T lymphocyte subsets in type I diabetes mellitus: analysis with anti-2H4 and anti-4B4 antibodies. Diabetes, 38, 1462–1468.
Faustman D., Li X., Lin H. Y., Fu Y., Eisenbarth G., Avruch J. and Guo J. (1991a): Linkage of faulty major histocompatibility complex class I to autoimmune diabetes. Science, 254, 1756–1761.
Faustman D., Schoenfeld D. and Ziegler R. (1991b): T-lymphocyte changes linked to autoan-tibodies: Association of insulin autoantibodies with CD4+CD45R+ lymphocyte subpopulation in prediabetic subjects. Diabetes, 40, 590–597.
Foulis A. K. (1987): C. L. Oakley lecture (1987). The pathogenesis of beta cell destruction in type I (insulin-dependent) diabetes mellitus. J. Pathol., 152, 141–148.
Franzoso G., Carlson L., Xing L., Poljak L., Shores E. W., Brown K. D., Leonardi A., Tran T., Boyce B. F. and Siebenlist U. (1997): Requirement for NF-κB in osteolast and B-cell development. Genes Dev., 11, 3482–3496.
Freland S., Chambers B. J., Andersson M., Van Kaer L. and Ljunggren H. G. (1998): Rejection of allogeneic and syngeneic but not MHC class I-deficient tumor grafts by MHC class I-deficient mice. J. Immunol., 160, 572–579.
Fruh K., Yang Y, Arnold D., Chambers J., Wu L., Waters J. B., Spies T. and Peterson P. A. (1992): Alternative exon usage and processing of the major histocompatibility complex-encoded proteasome subunits. J. Biol. Chem., 267, 22131–22140.
Fu Y, Nathan D. M., Li F., Li X. and Faustman D. L. (1993): Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity. J. Clin. Invest., 91, 2301–2307.
Fu Y, Yan G., Shi L. and Faustman D. (1998): Antigen processing and autoimmunity. Evaluation of mRNA abundance and function of HLA-linked genes. Ann. NY Acad. Sci., 842, 138–155.
Gaczynska M., Goldberg A. L., Tanaka K., Hendil K. B. and Rock K. L. (1996): Proteasome subunits X and Y alter peptidase activities in opposite ways to the interferon-gamma-induced subunits LMP2 and LMP7. J. Biol. Chem., 271, 17275–17280.
Ghosh S. and Baltimore D. (1990): Activation in vitro of NF-κB by phosphorylation of its inhibitor IκB. Nature, 344, 678–682.
Glas R., Ohlen C., Hoglund P. and Karre K. (1994): The CD8+ T cell repertoire in ß2-micro-globulin-deficient mice is biased towards reactivity against self-major histocompatibility complex class I. J. Exp. Med., 179, 661–672.
Goldberg A. L. (1995): Functions of the proteasome: the lysis at the end of the tunnel. Science, 268, 522–523.
Griffin T. A., Nandi D., Cruz M., Fehling H. J., Van Kaer L., Monaco J. J. and Colbert R. A. (1998): Immunoproteasome assembly: Cooperative incorporation of interferon γ (IFN-γ)-inducible subunits. J. Exp. Med., 187, 97–104.
Hanafusa T., Miyazaki A., Miyagawa J., Tamura S., Inada M., Yamada K., Shinji Y, Katsura H., Yamagata K. and Itoh N. (1990): Examination of islets in the pancreas biopsy specimens from newly diagnosed type 1 (insulin-dependent) diabetic patients. Diabetologia, 33, 105–111.
Hayashi T. and Faustman D. (1999): NOD mice are defective in proteasome production and activation of NF-κB. Mol. Cell. Biol., 19, 8646–8659.
Hayashi T. and Faustman D. (2000): Essential role of HLA-encoded proteasome subunits in NF-κB activation and prevention of TNF-α induced apoptosis. J. Biol. Chem., 275, 5238–5247.
Hayashi T., Sekine T. and Okamoto T. (1993a): Identification of a new serine kinase that activates NF-kappa B by direct phosphorylation. J. Biol. Chem., 268, 26790–26795.
Hayashi T., Ueno Y. and Okamoto T. (1993b): Oxireductive regulation of nuclear factor κB, involvement of a cellular reducing catalyst thioredoxin. J. Biol. Chem., 268, 11380–11388.
Hisamatsu H., Shimbara N., Saito Y, Kristensen P., Hendil K. B., Fujiwara T., Takahashi E., Tanahashi N., Tamura T., Ichihara A. and Tanaka K. (1996): Newly identified pair of proteasomal subunits regulated reciprocally by interferon-γ. J. Exp. Med., 183, 1807–1816.
Horwitz B. H., Scott M. L., Cherry S. R., Bronson R. T. and Baltimore D. (1997): Failure of lymphopoiesis after adoptive transfer of NF-kappaB-deficient fetal liver cells. Immunity, 6, 765–772.
Hu Y, Baud V., Delhase M., Zhang P., Deerinck T., Ellisman M., Johnson R. and Karin M. (1999): Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science, 284, 316–320.
Iotsova V., Caamano J., Loy J., Yang Y, Lewin A. and Bravo R. (1997): Osteopetrosis in mice lacking NF-kappaB 1 and NF-kappaB2. Nat. Med., 3, 1285–1289.
Jansen A., Van Hagen M. and Drexhage H. A. (1995): Defective maturation and function of antigen-presenting cells in type I diabetes. Lancet, 345, 491–492.
Kanegae Y, Ransone L. J., Wamsley P., Schmitt M. J., Boyer T. G., Zhou Q., Berk A. J. and Verma I. M. (1998): Role of Rel/NF-κB transcription factors during the outgrowth of the vertebrate limb. Nature, 392, 611–614.
Kay T. W. H., Campbell I. L., Oxbrow L. and Harrison L. C. (1991): Overexpression of class I major histocompatibility complex accompanies insulitis in the nonobese diabetic mouse and is prevented by anti-interferon-γ antibody. Diabetologia, 34, 779–785.
Kontgen F., Grumont R. J., Strasser A., Metcalf D., Li R., Tarlinton D. and Gerondakis S. (1995): Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev., 9, 1965–1977.
Li F., Hauser S. L., Linan M. J., Stein M. C. and Faustman D. L. (1995): Reduced expression of peptide-loaded HLA class I molecules on multiple sclerosis lymphocytes. Ann. Neurol., 38, 147–154.
Li Q., Lu Q., Hwang J. Y, Buscher D., Lee K. F, Izpisua-Belmonte J. C. and Verma I. M. (1999a): IKK 1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev., 13, 1322–1328.
Li Q., Van Antwerp D., Mercurio F., Lee K. F. and Verma I. M. (1999b): Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science, 284, 321–325.
Li X. and Faustman D. (1993): Use of donor β2-microglobulin-deficient transgenic mouse liver cells for isografts, allografts, and xenografts. Transplantation, 55, 940–946.
Lin J., Tserng K., Chen C, Lin L. and Tung T (1970): Abrin and ricin: new anti-tumor sub-stances. Nature, 227, 292–293.
Lin L., De Martino G. N. and Greene W. C. (1998): Co-translational biogenesis of NF-kappa B p50 by the 26S proteasome. Cell, 92, 819–828.
MacKichan M. L., Logeat F. and Israel A. (1996): Phosphorylation of p105 PEST sequences via a Redox-insensitive pathway up-regulates processing of p50 NF-κB. J. Biol. Chem., 271, 6084–6091.
Makino S., Kunimoto K., Muraoka Y, Mizushima Y, Katagiri K. and Tochino Y (1980): Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu. Exp. Animals, 29, 1–13.
Maniatis T. (1999): A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev., 13, 505–510.
Naumann N. and Scheidereit C. (1994): Activation of NF-κB in vivo is regulated by multiple phosphorylations. EMBO J., 13, 4597–4607.
Neri A., Chang C. C, Lombardi L., Salina M., Corradini P., Maiolo A. T., Chaganti R. S. and Dalla-Favera R. (1991): B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell, 67, 1075–1087.
Ono S. J., Issa-Chergui B., Colle E., Guttmann R. D., Seemayer T. A. and Fuks A. (1988): IDDM in BB rats. Enhanced MHC class I heavy-chain gene expression in pancreatic islets. Diabetes, 37, 1411–1418.
Orian A., Whiteside S., Israel A., Stancovski I., Schwartz A. L. and Ciechanover A. (1995): Ubiquitin-mediated processing of NF-kappa B transcriptional activator precursor p105. Reconstitution of a cell-free system and identification of the ubiquitin-carrier protein, E2, and a novel ubiquitin-protein ligase, E3, involved in conjugation. J. Biol. Chem., 270, 21707–21714.
Pahl H. L. and Baeuerle P. A. (1996): Control of gene expression by proteolysis. Curr. Opin. Cell Biol., 8, 340–347.
Palombella V., Rando O. J., Goldberg A. L. and Maniatis T. (1994): The ubiquitin-proteasome pathway is required for processing the NF-κB 1 precursor protein and the activation of NF-κB. Cell, 78, 773–785.
Rabinovitch A. and Skyler J. S. (1998): Prevention of type 1 diabetes. Med. Clin. North Am., 82, 739–755.
Schmid R. M., Perkins N. D., Duckett C. S., Andrews P. C. and Nabel G. J. (1991): Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature, 352, 733–736.
Sears C, Olesen J., Rubin D., Finley D. and Maniatis T. (1998): NF-κB p105 processing via the ubiquitin-proteasome pathway. J. Biol. Chem., 273, 1409–1419.
Sha W. C, Liou H. C., Tuomanen E. I. and Baltimore D. (1995): Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell, 80, 321–330.
Smerdon R. A., Peakman M., Hussain M. J., Alviggi L., Watkins P. J., Leslie D. G. and Vergani D. (1993): Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM. Diabetes, 42, 127–133.
Snapper C. M., Zelazowski P., Rosas F. R., Kehry M. R., Tian M., Baltimore D. and Sha W. C. (1996): B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J. Immunol., 156, 183–191.
Stephens L. A., Thomas H. E. and Kay T. W. (1997): Protection of NIT-1 pancreatic beta-cells from immune attack by inhibition of NF-kappaB. J. Autoimmun., 10, 293–298.
Sun S. C., Ganchi P. A., Beraud C., Ballard D. W. and Greene W. C. (1994): Autoregulation of the NF-kappa B transactivator RelA (p65) by multiple cytoplasmic inhibitors containing ankyrin motifs. Proc. Natl. Acad. Sci. USA, 91, 1346–1350.
Takeda K., Takeuchi O., Tsujimura T, Itami S., Adachi O., Kawai T., Sanjo H., Yoshikawa K., Terada N. and Akira S. (1999): Limb and skin abnormalities in mice lacking IKKalpha. Science, 284, 313–316.
Tan T. H., Huang G. P., Sica A., Ghosh P., Young H. A., Longo D. L. and Rice N. R. (1992): Kappa B site-dependent activation of the interleukin-2 receptor alpha-chain gene promoter by human C-Rel. Mol. Cell. Biol., 12, 4067–4075.
Tanaka M., Fuentes M. E., Yamaguchi K., Durnin M. H., Dalrymple S. A., Hardy K. L. and Goeddel D. V. (1999): Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity, 10, 421–429.
Thanos D. and Maniatis T (1995): NF-kappa B: a lesson in family values. Cell, 80, 529–532.
Van Antwerp D. J., Martin S. J., Kafri T, Green D. R. and Verma I. M. (1996): Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science, 274, 787–789.
Van Kaer L., Ashton-Rickardt P. G., Eichelberger M., Gaczynska M., Nagashima K., Rock K. L., Goldberg A. L., Doherty P. C. and Tonegawa S. (1994): Altered peptidase and viral-specific T cell response in LMP-2 mutant mice. Immunity, 1, 533–541.
Verma I. M., Stevenson E. M., Schwarz D. V., Antwerp S. and Miyamoto S. (1995): Rel/NF—kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev., 9, 2723–2735.
Vidal-Puig A. and Faustman D. L. (1994): Tolerance to peripheral tissue is transient and maintained by tissue specific class I expression. Transplant. Proc, 26, 3314–3316.
Vives-Pi M, Armengol M. P., Alcalde L., Costa M., Somoza N., Vargas F., Jaraquemada D. and Pujol-Borrell R. (1996): Expression of transporter associated with antigen processing-1 in the endocrine cells of human pancreatic islets: effect of cytokines and evidence of hyperex-pression in IDDM. Diabetes, 45, 779–788.
Wakatsuki Y., Neurath M. F., Max E. E. and Strober W. (1994): The B cell-specific transcription factor BSAP regulates B cell proliferation. J. Exp. Med., 179, 1099–1108.
Wang C. Y., Mayo M. W. and Baldwin A. S. (1996): TNF and cancer therapy-induced apoptosis potentiation by inhibition of NF-kappaB. Science, 274, 784–787.
Weih F., Carrasco D., Durham S. K., Barton D. S., Rizzo C. A., Ryseck R. P., Lira S. A. and Bravo R. (1995): Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell, 80, 331–340.
Weringer E. J. and Like A. A. (1988): Identification of T cell subsets and class I and class II antigen expression in islet grafts and pancreatic islets of diabetic BioBreeding/Worcester rats. Am. J. Pathol., 132, 292–303.
Wu M., Lee H., Bellas R. E., Schauer S. L., Arsura M., Katz D., Fitzgerald M. J., Rothstein T. L., Sherr D. H. and Sonenshein G. E. (1996): Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells. EMBO J., 15, 4682–4690.
Yan G., Fu Y. and Faustman D. L. (1997): Reduced expression of Tap1 and Lmp2 antigen processing genes in the nonobese diabetic (NOD) mouse due to a mutation in their shared bidirectional promoter. J. Immunol., 159, 3068–3080.
Yang X. D., Tisch R., Singer S. M., Cao Z. A., Liblau R. S., Schreiber R. D. and McDevitt H. O. (1994): Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J. Exp. Med., 180, 995–1004.
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Hayashi, T., Faustman, D. (2001). A Role for NF-κB and the Proteasome in Autoimmunity. In: Górski, A., Krotkiewski, H., Zimecki, M. (eds) Autoimmunity. Springer, Dordrecht. https://doi.org/10.1007/978-94-010-0981-2_5
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