Inosine-containing dsRNA binds a stress-granule-like complex and downregulates gene expression in trans

Area of Science:

• Molecular Biology
• Gene Regulation
• RNA Modification

Background:

• Adenosine deaminases acting on RNA (ADARs) extensively modify long double-stranded RNAs (dsRNAs) through hyperediting, converting adenosine (A) to inosine (I).
• The functional consequences of A-to-I hyperediting were traditionally considered limited to the modified RNA molecule itself.

Purpose of the Study:

• To investigate the non-cell-autonomous effects of hyperedited dsRNA (I-dsRNA) on gene expression.
• To elucidate the mechanisms by which I-dsRNA influences gene expression, including mRNA levels and translation.

Main Methods:

• Utilizing reporter gene assays to assess the impact of I-dsRNA on gene expression.
• Analyzing mRNA levels and translation efficiency in the presence of I-dsRNA.
• Investigating the interaction of I-dsRNA with cellular complexes, specifically stress granules.

Main Results:

• Hyperedited dsRNA (I-dsRNA) significantly downregulates gene expression in trans.
• Both endogenous and reporter gene expression are reduced by I-dsRNA.
• I-dsRNA inhibits translation initiation and reduces reporter mRNA levels.
• I-dsRNA specifically binds to stress-granule-like complexes, which are involved in translational silencing.

Conclusions:

• ADAR-mediated RNA editing of dsRNA can lead to potent gene silencing.
• I-dsRNA induces downregulation of gene expression through translational inhibition and stress granule formation.
• This study proposes a novel model where RNA editing by ADARs contributes to gene expression regulation via stress granule pathways.