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

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.