RNase L Reprograms Translation by Widespread mRNA Turnover Escaped by Antiviral mRNAs

Area of Science:

• Molecular Biology
• Immunology
• Cellular Biology

Background:

• Protein kinase R (PKR) and ribonuclease L (RNase L) are key mediators of cellular responses to double-stranded RNA (dsRNA).
• PKR inhibits translation initiation and promotes stress granule formation, while RNase L's role in translation repression and stress granule assembly remains unclear.
• Understanding RNase L's mechanisms is crucial for deciphering cellular defense against viral infections and other dsRNA stimuli.

Purpose of the Study:

• To elucidate the mechanisms by which RNase L represses translation in response to dsRNA.
• To investigate RNase L's role in stress granule assembly and the regulation of dsRNA-induced mRNAs.
• To identify how RNase L reprograms translation during dsRNA stress.

Main Methods:

• Utilized mammalian cell models to study the effects of dsRNA exposure.
• Analyzed mRNA turnover, translation reprogramming, and stress granule dynamics.
• Investigated the resistance of specific mRNAs, including antiviral interferon-beta (IFN-β), to RNase L-mediated degradation.

Main Results:

• RNase L induces translational shut-off by promoting widespread mRNA turnover in response to dsRNA.
• This mRNA degradation alters stress granule assembly and reprograms translation.
• Antiviral mRNAs, such as IFN-β, exhibit resistance to RNase L degradation, enabling their translation.

Conclusions:

• RNase L reprograms translation during dsRNA stress primarily through bulk mRNA degradation.
• The selective resistance of antiviral mRNAs to RNase L is a key mechanism for mounting an antiviral response.
• Cellular responses to dsRNA vary between individual cells, impacting cellular outcomes.