Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis

Area of Science:

• Molecular Biology
• Genetics
• Immunology

Background:

• Adenosine-to-inosine (A-to-I) RNA editing by ADAR proteins is a key epitranscriptomic modification.
• While ADAR2's role in protein recoding is established, ADAR1's essential functions, including editing-dependent and independent roles, remain unclear.
• ADAR1 critically prevents self-RNA from activating the MDA5 innate immune sensor.

Purpose of the Study:

• To investigate the in vivo consequences of ADAR1 editing deficiency on murine homeostasis.
• To determine the relative contributions of ADAR1's editing-dependent and independent functions.
• To assess ADAR1's role in organismal homeostasis outside of its function in preventing MDA5 activation.

Main Methods:

• Generation and analysis of Adar1 ^E861A/E861A Ifih1 ^-/- mice, which lack ADAR1 editing activity but retain MDA5.
• Assessment of A-to-I editing across various adult murine tissues.
• Comparative analysis of Adar1 ^-/- and Adar1 ^E861A/E861A alleles on both Ifih1 ^+/+ and Ifih1 ^-/- backgrounds.

Main Results:

• Mice lacking ADAR1 editing activity (Adar1 ^E861A/E861A) in the absence of MDA5 (Ifih1 ^-/-) exhibited normal lifespan and homeostasis.
• A mild, non-pathogenic innate immune activation signature was observed in these mice.
• ADAR1 performs the majority of RNA editing in most tissues, with limited compensation by ADAR2.
• ADAR1 editing-independent functions appear to contribute minimally to homeostasis.

Conclusions:

• Lifetime absence of ADAR1-mediated RNA editing is well-tolerated in mice lacking MDA5.
• ADAR1-dependent protein recoding is not essential for organismal homeostasis.
• Phenotypes associated with ADAR1 loss result from RNA editing and MDA5-dependent immune activation.