Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing
Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing
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DOI：
10.1074/jbc.m500476200
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发表时间：
2005-04-15
影响因子：
4.8
通讯作者：
Samuel, CE
中科院分区：
文献类型：
--
作者：
George, CX;Wagner, MV;Samuel, CE
ADAR 1（腺苷脱氨酶作用于RNA）在成年哺乳动物中广泛表达，并在胚胎发育过程中起关键作用。已知具有腺苷-肌苷编辑活性的两种大小形式的ADAR 1：类似于150-kDa蛋白的干扰素（IFN）诱导型和类似于110-kDa蛋白的组成型表达的N-末端截短型。我们定义了小鼠Adar 1基因的5 '侧翼区的结构，并且我们在这里显示小鼠Adar 1转录物具有从独特启动子起始并剪接到共同外显子2接合处的选择性外显子1结构（1A、1B和1C）。含有外显子1A的编码p150的转录本在成年小鼠检查的所有组织（脑、盲肠、心脏、肾脏、肝脏、肺、脾脏和派尔集合淋巴结）中表达，并且在肝脏中升高最显着，但在口腔感染沙门氏菌后在大脑中保持最低水平。含外显子1B的RNA在脑中最丰富，在感染后检查的任何组织中均未增加。含外显子1C的RNA非常稀少。外显子1A，而不是外显子1B或1C，表达增加，在成纤维细胞L细胞与IFN治疗，和共识ISRE元件存在于驱动外显子1A表达的启动子。外显子1B在胚胎10.5天的胚胎中可检测到，但在胚胎15天的胚胎中大量表达，而外显子1A则未检测到。此外，ADAR 1 p110蛋白亚型在胚胎组织中检测到，而p110和诱导型p150蛋白在IFN处理的L细胞中被发现。最后，选择性外显子7a的存在与包含外显子1B的RNA相关，并且选择性外显子7 b与包含外显子1A的RNA相关。这些结果表明，多个启动子驱动Adar 1基因在成年小鼠中的表达，IFN诱导型启动子和外显子1A的RNA主要负责增加的ADAR 1沙门氏菌感染的小鼠中观察到的，和组成型外显子1B的转录本和编码的p110蛋白产物在成年大脑和胚胎发育过程中大量表达。
ADAR1 ( adenosine deaminase acting on RNA) is widely expressed in adult mammals and has a critical role during embryogenesis. Two size forms of ADAR1 are known that possess adenosine-to-inosine editing activity: an interferon (IFN)-inducible similar to 150-kDa protein and a constitutively expressed N-terminally truncated similar to 110-kDa protein. We defined the structure of the 5'-flanking region of the mouse Adar1 gene, and we show here that mouse Adar1 transcripts possess alternative exon 1 structures (1A, 1B, and 1C) that initiate from unique promoters and are spliced to a common exon 2 junction. Exon 1A-containing transcripts encoding p150 were expressed in all tissues examined from adult mice ( brain, cecum, heart, kidney, liver, lung, spleen, and Peyer's patches) and were elevated most significantly in liver but remained lowest in brain following oral infection with Salmonella. Exon 1B-containing RNA was most abundant in brain and was not increased in any tissue examined following infection. Exon 1C-containing RNA was very scarce. Exon 1A, but not exon 1B or 1C, expression was increased in fibroblast L cells treated with IFN, and a consensus ISRE element was present in the promoter driving exon 1A expression. Exon 1B, but not 1A, was detectable in embryonic day 10.5 embryos and was abundantly expressed in embryonic day 15 embryos. Furthermore, the ADAR1 p110 protein isoform was detected in embryonic tissue, whereas both p110 and the inducible p150 proteins were found in IFN-treated L cells. Finally, the presence of alternative exon 7a correlated with exon 1B-containing RNA, and alternative exon 7b correlated with exon 1A-containing RNA. These results establish that multiple promoters drive the expression of the Adar1 gene in adult mice, that the IFN inducible promoter and exon 1A-containing RNA are primarily responsible for the increased ADAR1 observed in Salmonella-infected mice, and that the constitutive exon 1B-containing transcript and encoded p110 protein product are abundantly expressed both in adult brain and during embryogenesis.