RNase L activation in the cytoplasm induces aberrant processing of mRNAs in the nucleus

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• The innate immune system employs RNase L (an endoribonuclease) to degrade host and viral RNA, limiting viral gene expression.
• RNase L activation is a key component of the cellular antiviral defense mechanism.

Purpose of the Study:

• To investigate the localization and consequences of RNase L activation on RNA processing and protein biogenesis.
• To elucidate the interplay between cytoplasmic RNA decay and nuclear RNA processing during viral infections.

Main Methods:

• Localization studies of RNase L and RNase L-mediated mRNA decay.
• Analysis of RNA-binding protein (RBP) translocation upon RNase L activation.
• Assessment of global RNA processing alterations in the nucleus.
• Examination of interferon mRNA processing and protein production.
• Investigation of RNA processing defects during dengue virus and SARS-CoV-2 infections.

Main Results:

• RNase L and its mRNA decay activity are primarily cytoplasmic.
• Activated RNase L induces RBP translocation from the cytoplasm to the nucleus.
• Nuclear RNA processing is globally altered, particularly affecting interferon mRNAs, leading to their nuclear retention.
• Interferon protein production is reduced.
• Similar RNA processing defects are observed during dengue virus and SARS-CoV-2 infections.

Conclusions:

• RNase L activation triggers a multi-step immune response that disrupts protein biogenesis.
• RBP distribution between nucleus and cytoplasm is dynamically regulated by RNA availability.
• Viral infections activating cytoplasmic RNase L induce nuclear RNA processing defects, creating a novel antiviral mechanism.