An internal deletion of ADAR rescued by MAVS deficiency leads to a minute phenotype

被引:36
作者
Bajad, Prajakta [1 ]
Ebner, Florian [1 ]
Amman, Fabian [1 ,2 ]
Szabo, Brigitta [1 ]
Kapoor, Utkarsh [1 ]
Manjali, Greeshma [1 ]
Hildebrandt, Aiwine [1 ]
Janisiw, Michael P. [1 ]
Jantsch, Michael F. [1 ]
机构
[1] Med Univ Vienna, Ctr Anat & Cell Biol, Dept Cell & Dev Biol, Schwarzspanierstr 17, A-1090 Vienna, Austria
[2] Univ Vienna, Inst Theoret Biochem, Wahringer Str 17, A-1090 Vienna, Austria
基金
奥地利科学基金会;
关键词
EDITING ENZYME ADAR1; ADENOSINE-DEAMINASE; UNWINDING ACTIVITY; LEPTIN RECEPTOR; GENE ENCODES; RNA; EXPRESSION; RESPONSES; MUTATION; CELLS;
D O I
10.1093/nar/gkaa025
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3286 / 3303
页数:18
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