NLR family member NLRC5 is a transcriptional regulator of MHC class I genes
NLR family member NLRC5 is a transcriptional regulator of MHC class I genes
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DOI：
10.1073/pnas.1008684107
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发表时间：
2010-08-03
影响因子：
11.1
通讯作者：
Kobayashi, Koichi S.
中科院分区：
文献类型：
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作者：
Meissner, Torsten B.;Li, Amy;Kobayashi, Koichi S.
MHC I 类通过向 CD8 T 细胞呈递抗原，在针对病毒和肿瘤的免疫防御中发挥着关键作用。 NLR 蛋白 II 类反式激活蛋白 (CIITA) 是 MHC II 类基因表达的关键调节因子，与 MHC II 类启动子中的转录因子相关联并协同作用。尽管 CIITA 也反式激活 MHC I 类基因启动子，但人类和小鼠中 CIITA 的缺失会导致仅 MHC II 类表达的严重减少，这表明有其他机制调节 MHC I 类的表达。在这里，我们确定了 NLR 蛋白家族的另一个成员 NLRC5，作为 MHC I 类基因的转录调节因子。与 CIITA 类似，NLRC5 是一种 IFN-γ 诱导型核蛋白，NLRC5 的表达导致淋巴和上皮细胞系中 MHC I 类表达增强。使用染色质免疫沉淀和报告基因检测，我们表明 NLRC5 与 MHC I 类基因的启动子相关联并激活它们。此外，我们发现，IFN-γ诱导的MHC I类上调需要NLRC5，因为NLRC5的敲低会特异性损害MHC I类的表达。除了MHC I类基因外，NLRC5还诱导β2-微球蛋白、与抗原加工相关的转运蛋白和大型多功能蛋白酶的表达，这些都是MHC所必需的 I 类抗原呈递。我们的结果表明 NLRC5 是一种转录调节因子，协调 MHC I 类通路中关键成分的协同表达。
MHC class I plays a critical role in the immune defense against viruses and tumors by presenting antigens to CD8 T cells. An NLR protein, class II transactivator (CIITA), is a key regulator of MHC class II gene expression that associates and cooperates with transcription factors in the MHC class II promoter. Although CIITA also transactivates MHC class I gene promoters, loss of CIITA in humans and mice results in the severe reduction of only MHC class II expression, suggesting that additional mechanisms regulate the expression of MHC class I. Here, we identify another member of the NLR protein family, NLRC5, as a transcriptional regulator of MHC class I genes. Similar to CIITA, NLRC5 is an IFN-gamma-inducible nuclear protein, and the expression of NLRC5 resulted in enhanced MHC class I expression in lymphoid as well as epithelial cell lines. Using chromatin immunoprecipitation and reporter gene assays, we show that NLRC5 associates with and activates the promoters of MHC class I genes. Furthermore, we show that the IFN-gamma-induced up-regulation of MHC class I requires NLRC5, because knockdown of NLRC5 specifically impaired the expression of MHC class I. In addition to MHC class I genes, NLRC5 also induced the expression of beta 2-microglobulin, transporter associated with antigen processing, and large multifunctional protease, which are essential for MHC class I antigen presentation. Our results suggest that NLRC5 is a transcriptional regulator, orchestrating the concerted expression of critical components in the MHC class I pathway.