An internal deletion of ADAR rescued by MAVS deficiency leads to a minute phenotype
An internal deletion of ADAR rescued by MAVS deficiency leads to a minute phenotype
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DOI：
10.1093/nar/gkaa025
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发表时间：
2020-04-06
影响因子：
14.9
通讯作者：
Jantsch, Michael F.
中科院分区：
文献类型：
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作者：
Bajad, Prajakta;Ebner, Florian;Jantsch, Michael F.
RNA编辑蛋白阿达尔对于小鼠的早期发育至关重要。遗传学证据表明，A到I编辑将内源性RNA标记为“自我”。如今，已经产生了不同的阿达尔敲除等位基因，其在E12.5时显示出细胞凋亡、肝崩解、升高的免疫应答和致死性的共同表型。所有的阿达尔敲除等位基因都可以通过伴随的先天免疫基因Mays或Ifihl（MDA 5）的缺失来挽救，尽管程度不同。这表明阿达尔具有多种功能。我们分析了阿达尔（德尔塔7 - 9）小鼠，显示出独特的生长缺陷表型时，挽救梅斯。我们发现Adar可以形成一种截短的、不稳定的、错误定位的编辑缺陷蛋白。这些小鼠的组织学和血液学分析表明存在多种组织和造血缺陷。基因表达谱显示Rps3a1和Rps3a3在拯救的阿达尔中失调（Delta 7 - 9）。一致地，在肝细胞中观察到40S和60S核糖体比率的畸变。在阿达尔（Delta 2 - 13）; Mays（-/-）小鼠中也观察到这种失调，但在阿达尔（E861 A/E861 A）; Ijih1（-）（/-）小鼠中未观察到，表明阿达尔在调节Rps3a1和Rps3a3表达水平方面具有编辑非依赖性功能。总之，我们的研究表明阿达尔在出生后发育中的重要性，ADARB1不能弥补。
The RNA-editing protein ADAR is essential for early development in the mouse. Genetic evidence suggests that A to I editing marks endogenous RNAs as 'self'. Today, different Adar knockout alleles have been generated that show a common phenotype of apoptosis, liver disintegration, elevated immune response and lethality at E12.5. All the Adar knockout alleles can be rescued by a concomitant deletion of the innate immunity genes Mays or Ifihl (MDA5), albeit to different extents. This suggests multiple functions of ADAR. We analyze Adar(Delta 7-9) mice that show a unique growth defect phenotype when rescued by Mays. We show that Adar'' can form a truncated, unstable, editing deficient protein that is mislocalized. Histological and hematologic analysis of these mice indicate multiple tissue- and hematopoietic defects. Gene expression profiling shows dysregulation of Rps3a1 and Rps3a3 in rescued Adar(Delta 7-9). Consistently, a distortion in 40S and 60S ribosome ratios is observed in liver cells. This dysregulation is also seen in Adar(Delta 2-13); Mays(-/-) but not in Adar(E861A/E861A); Ijih1(-)(/-) mice, suggesting editing-independent functions of ADAR in regulating expression levels of Rps3a1 and Rps3a3. In conclusion, our study demonstrates the importance of ADAR in post-natal development which cannot be compensated by ADARB1.