Reduced expression of Tap1 and Lmp2 antigen-processing genes in the nonobese diabetic (NOD) mouse due to a mutation in their shared bidirectional promoter.
Reduced expression of Tap1 and Lmp2 antigen-processing genes in the nonobese diabetic (NOD) mouse due to a mutation in their shared bidirectional promoter.
复制标题
DOI：
10.4049/jimmunol.159.6.3068
复制
发表时间：
1997-09
影响因子：
4.4
通讯作者：
G. Yan;Y. Fu;D. Faustman
中科院分区：
文献类型：
--
作者：
G. Yan;Y. Fu;D. Faustman
MHC是自身免疫的重要贡献者。Lmp 2和Tap 1是位于MHC II类区域中的基因，并且它们编码参与用于T细胞教育的内源性肽的产生和运输的蛋白质。在非肥胖糖尿病（NOD）小鼠中，现已检测到Lmp 2和Tap 1基因的共同双向启动子中的突变（T->A）。NOD小鼠中的核苷酸取代（TCATTC-->TCAATC）消除了被认为对RNA聚合酶II在Lmp 2方向上的定位很重要的起始（Inr）元件（TCATTC）。它还分别在Lmp 2和Tap 1方向上创建了一个CAAT样盒和一个反向CAAT样盒。北方印迹显示NOD小鼠中Tap 1和Lmp 2 mRNA的量减少，并且cDNA末端的5 '-快速扩增显示这些动物中Lmp 2的转录起始位点的丢失。来自NOD小鼠的Tap 1-Lmp 2启动子在使用Tap 1和Lmp 2基因的荧光素酶报告构建体的瞬时转染测定中显示出降低的转录活性。从NOD小鼠分离的含有Lmp 2的蛋白酶体观察到的底物特异性改变与Lmp 2活性降低一致。非MHC基因（NOR小鼠）和性别因素（雄性NOD小鼠）影响启动子多态性的有利影响进一步证实了突变的基本性别和激素背景。这项研究确定了NOD小鼠MHC中的第一个特定突变，该突变特异性地影响参与肽呈递的基因的活性，肽呈递是T细胞教育所必需的过程。
The MHC is an essential contributor to autoimmunity. Lmp2 and Tap1 are genes located in the MHC class II region, and they encode proteins participating in the generation and transport of endogenous peptides for T cell education. A mutation (T-->A) has now been detected in the shared bidirectional promoter of the Lmp2 and Tap1 genes in the nonobese diabetic (NOD) mouse. The nucleotide substitution (TCATTC-->TCAATC) in NOD mice eliminates an initiator (Inr) element (TCATTC) thought to be important for RNA polymerase II positioning in the Lmp2 orientation. It also created a CAAT-like box and an inverted CAAT-like box in the Lmp2 and Tap1 orientations, respectively. Northern blot revealed reduced amounts of Tap1 and Lmp2 mRNA in NOD mice, and 5'-rapid amplification of cDNA ends revealed the loss of a transcription start site of Lmp2 in these animals. The Tap1-Lmp2 promoter from NOD mice showed reduced transcriptional activity in transient transfection assays with luciferase reporter constructs for both Tap1 and Lmp2 genes. Observed altered substrate specificity of Lmp2 containing proteasomes isolated from NOD mice was consistent with reduced Lmp2 activity. The beneficial influence of non-MHC genes (NOR mice) and gender factors (male NOD mice) influencing the penetrance of the promoter polymorphism further confirmed the essential gender and hormonal context of the mutation. This study identifies the first specific mutation in the MHC of the NOD mouse that specifically impacts the activity of genes involved in peptide presentation, a process essential for T cell education.