<br>作用于 RNA (ADAR) 酶的腺苷脱氨酶：从怪异到奇妙的旅程,Accounts of Chemical Research

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作用于 RNA (ADAR) 酶的腺苷脱氨酶：从怪异到奇妙的旅程
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2023-10-31 , DOI: 10.1021/acs.accounts.3c00433
Liam P Keegan ₁ , Khadija Hajji ₁ , Mary A O'Connell ₁

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作用于 RNA 的腺苷脱氨酶 (ADAR) 催化双链 (ds)RNA 中腺苷转化为肌苷，该酶在进化上是保守的，对于许多生物功能（包括神经系统功能、造血和先天免疫）至关重要。最初，人们认为 ADAR 的广泛生物学作用是由于 mRNA 中的肌苷被翻译机器读取为鸟苷，从而允许目标密码子中不完整的 RNA 编辑从同一初级转录物生成两种不同的蛋白质。在人类中，大约有 76 个位置在组织中以超过 20% 的效率进行位点特异性编辑，从而导致重新编码。其中许多转录本在中枢神经系统 (CNS) 中表达并由 ADAR2 编辑。利用小鼠遗传模型发现，缺乏 Adar2 编码基因的转基因小鼠会在出生后 3 周内死亡。因此，ADAR2 在神经系统中产生蛋白质多样性方面的作用是明确的，但为什么 ADAR RNA 编辑活动在其他生物过程中至关重要，特别是主要涉及 ADAR1 的编辑？ ADAR1 编辑嵌入 Alu 元件反向重复序列 (AluIR) 的人类转录本，但此活动与先天免疫激活的联系尚不清楚。缺乏编码Adar1基因的小鼠在胚胎阶段是致命的，一项重大突破是发现Adar1在先天免疫中的作用是由于它能够编辑这种重复元件反向重复序列，而这些重复元件能够在转录物中形成dsRNA。肌苷的存在可防止 dsRNA 传感器黑色素瘤分化相关蛋白 5 (Mda5) 的激活。因此，肌苷帮助细胞区分自身 RNA 和非自身 RNA，就像 mRNA 上的条形码一样。由于先天免疫是许多不同生物过程的关键，ADAR1 酶这种广泛的生物学作用的基础变得显而易见。

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Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous

The adenosine deaminase acting on RNA (ADAR) enzymes that catalyze the conversion of adenosine to inosine in double-stranded (ds)RNA are evolutionarily conserved and are essential for many biological functions including nervous system function, hematopoiesis, and innate immunity. Initially it was assumed that the wide-ranging biological roles of ADARs are due to inosine in mRNA being read as guanosine by the translational machinery, allowing incomplete RNA editing in a target codon to generate two different proteins from the same primary transcript. In humans, there are approximately seventy-six positions that undergo site-specific editing in tissues at greater than 20% efficiency that result in recoding. Many of these transcripts are expressed in the central nervous system (CNS) and edited by ADAR2. Exploiting mouse genetic models revealed that transgenic mice lacking the gene encoding Adar2 die within 3 weeks of birth. Therefore, the role of ADAR2 in generating protein diversity in the nervous system is clear, but why is ADAR RNA editing activity essential in other biological processes, particularly editing mainly involving ADAR1? ADAR1 edits human transcripts having embedded Alu element inverted repeats (AluIRs), but the link from this activity to innate immunity activation was elusive. Mice lacking the gene encoding Adar1 are embryonically lethal, and a major breakthrough was the discovery that the role of Adar1 in innate immunity is due to its ability to edit such repetitive element inverted repeats which have the ability to form dsRNA in transcripts. The presence of inosine prevents activation of the dsRNA sensor melanoma differentiation-associated protein 5 (Mda5). Thus, inosine helps the cell discriminate self from non-self RNA, acting like a barcode on mRNA. As innate immunity is key to many different biological processes, the basis for this widespread biological role of the ADAR1 enzyme became evident.

更新日期：2023-10-31

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