NOD mice are defective in proteasome production and activation of NF-kappaB.
NOD mice are defective in proteasome production and activation of NF-kappaB.
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NOD 小鼠在蛋白酶体产生和 NF-κB 激活方面存在缺陷。
DOI：
10.1128/mcb.19.12.8646
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发表时间：
1999
影响因子：
5.3
通讯作者：
Faustman,D
中科院分区：
文献类型：
--
作者：
Hayashi,T;Faustman,D
非肥胖型糖尿病（NOD）小鼠是人类I型糖尿病的动物模型，具有与基因组的主要组织相容性复合体（MHC）映射的强遗传成分。我们已经确定了NOD淋巴细胞中的一个特定的蛋白酶体缺陷，导致缺乏LMP 2亚基。显著的蛋白酶体缺陷导致转录因子NF-κB的产生和激活缺陷，NF-κB在免疫和炎症反应以及防止肿瘤坏死因子α诱导的细胞凋亡中起重要作用。NOD小鼠脾细胞中蛋白酶体功能的缺陷是明显的，通过蛋白水解加工受损的NF-κB B亚基p50和p52产生以及NF-κ B抑制蛋白IκBα的降解受损。MHC连接的蛋白酶体亚基在转录因子加工和激活中的强制性作用已经在自发性疾病模型和同样缺乏MHC编码亚基的突变细胞中建立。这些数据表明，NOD蛋白酶体功能障碍是由于组织和发育阶段特异性缺陷的MHC-linkedLmp 2基因的表达，导致转录因子NF-κB的活性改变，这种缺陷有助于NOD小鼠的发病机制。这些观察结果与I型糖尿病的多样性代谢学一致，并表明这种错误的表达存在明显的性别、组织和年龄特异性差异，这与胰岛素依赖性（I型）糖尿病的发病和病程平行。
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-κB, 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-κB subunit p50 and p52 generation by proteolytic processing and impaired degradation of the NF-κB-inhibitory protein IκBα. 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-linkedLmp2gene, resulting in altered transcription factor NF-κB 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.