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Molecular and Cellular Biology, December 1999, p. 8646-8659, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

NOD Mice Are Defective in Proteasome Production and Activation of NF-kappa B

Takuma Hayashi and Denise Faustman*

Immunobiology Laboratory, Massachusetts General Hospital-East, and Harvard Medical School, Charlestown, Massachusetts 02129

Received 9 June 1999/Returned for modification 6 July 1999/Accepted 22 September 1999

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-kappa B, 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-kappa B subunit p50 and p52 generation by proteolytic processing and impaired degradation of the NF-kappa B-inhibitory protein Ikappa Balpha . 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-kappa B 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.

* Corresponding author. Mailing address: Immunology Laboratory, Massachusetts General Hospital-East, Building 149, 13th St., Charlestown, MA 02129. Phone: (617) 726-4084. Fax: (617) 726-4095. E-mail: denise.faustman{at}cbrc2.mgh.harvard.edu.

Molecular and Cellular Biology, December 1999, p. 8646-8659, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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