ADAR1介导的A-to-I RNA编辑丢失后的细胞死亡不受内在凋亡途径的影响。,Cell Death & Disease

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ADAR1介导的A-to-I RNA编辑丢失后的细胞死亡不受内在凋亡途径的影响。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-12-04 , DOI: 10.1038/s41419-019-2160-6
Carl R Walkley _{1,

2,

3} , Benjamin T Kile _{4,

5}

Affiliation

RNA的修饰（统称为表观转录组）广泛存在，在进化上是保守的，并且有助于健康和疾病状态下的基因调节和蛋白质多样性。描述了超过160种RNA修饰，大大超过了DNA修饰的数量。其中，腺苷到肌苷（A到I）的RNA编辑是最常见的一种。鼠标中有成千上万个A-to-I编辑站点，而人类中则有数百万个。翻译或测序后，肌苷碱基被解码为鸟苷，导致RNA和DNA之间的A到G错配。肌苷与腺苷具有不同的碱基配对特性，因此编辑不仅会改变RNA编码，而且还会改变RNA结构。在哺乳动物中，ADAR1和ADAR2进行A对I编辑。小鼠功能ADAR1等位基因丧失的特征是细胞死亡和无法存活的胚胎发生。Adar1-/-和编辑缺陷型（Adar1E861A / E861A）小鼠在造血功能衰竭的E11.75-13.5之间死亡。令人惊讶的是，该表型通过胞质dsRNA传感器MDA5或其下游衔接子MAVS的缺失而得以挽救，这种机制在人和小鼠中都得到了保留。当前文献表明，ADAR1的丢失通过细胞凋亡导致细胞死亡，但是这尚未在遗传学上得到证实。我们报告说，内在的（线粒体）凋亡途径的阻断通过BAK和BAX的丢失，不会挽救或改变胎儿肝脏的细胞表型，也不会延长ADAR1编辑缺陷胚胎的寿命。我们曾预计，BAK和BAX的损失将挽救或至少大大延长 Adar1E861A / E861A胚胎的孕育能力。但是，在E13.5恢复的三重突变型Adar1E861A / E861A Bak-/-Bax-/-胚胎与带有BAK和BAX的Adar1E861A / E861A胚胎没有区别。结果表明，不需要内在凋亡途径的细胞死亡过程是由ADAR1丢失后的MDA5触发的。

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Cell death following the loss of ADAR1 mediated A-to-I RNA editing is not effected by the intrinsic apoptosis pathway.

Modifications of RNA, collectively termed as the epitranscriptome, are widespread, evolutionarily conserved and contribute to gene regulation and protein diversity in healthy and disease states. There are >160 RNA modifications described, greatly exceeding the number of modifications to DNA. Of these, adenosine-to-inosine (A-to-I) RNA editing is one of the most common. There are tens of thousands of A-to-I editing sites in mouse, and millions in humans. Upon translation or sequencing an inosine base is decoded as guanosine, leading to A-to-G mismatches between the RNA and DNA. Inosine has different base pairing properties to adenosine and as a result editing not only alters the RNA code but can also change the RNA structure. In mammals A-to-I editing is performed by ADAR1 and ADAR2. A feature of murine loss of function ADAR1 alleles is cell death and a failure to survive embryogenesis. Adar1-/- and editing deficient (Adar1E861A/E861A) mice die between E11.75-13.5 of failed hematopoiesis. Strikingly this phenotype is rescued by the deletion of the cytosolic dsRNA sensor MDA5 or its downstream adaptor MAVS, a mechanism conserved in human and mouse. Current literature indicates that the loss of ADAR1 leads to cell death via apoptosis, yet this has not been genetically established. We report that blockade of the intrinsic (mitochondrial) apoptosis pathway, through the loss of both BAK and BAX, does not rescue or modify the cellular phenotype of the fetal liver or extend the lifespan of ADAR1 editing deficient embryos. We had anticipated that the loss of BAK and BAX would rescue, or at least significantly extend, the gestational viability of Adar1E861A/E861A embryos. However, the triple mutant Adar1E861A/E861A Bak-/- Bax-/- embryos that were recovered at E13.5 were indistinguishable from the Adar1E861A/E861A embryos with BAK and BAX. The results indicate that cell death processes not requiring the intrinsic apoptosis pathway are triggered by MDA5 following the loss of ADAR1.

更新日期：2019-12-04

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