Drosha as an interferon-independent antiviral factor

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Small interfering RNAs (siRNAs) are known antiviral mechanisms in invertebrates and plants.
• The role of host small RNA machinery in mammalian antiviral responses remains largely unexplored.
• Dicer and Drosha are RNase III enzymes essential for small RNA biogenesis.

Purpose of the Study:

• To investigate the interplay between host small RNA machinery and cellular antiviral responses in mammals.
• To determine the specific roles of Dicer and Drosha in combating viral infections.

Main Methods:

• Evaluation of antiviral activity in cells with and without functional Dicer or Drosha.
• Analysis of Drosha localization and function during viral infection.
• Assessment of viral RNA levels, viral small RNA production, and host transcriptome changes.

Main Results:

• Loss of Dicer did not affect the cellular antiviral response.
• Drosha deletion significantly increased viral RNA levels.
• Diverse RNA viruses induce exportin 1 (XPO1/CRM1)-dependent Drosha translocation to the cytoplasm, independent of protein synthesis or type I IFN.
• Increased viral infection in Drosha-deficient cells correlated with viral genomic RNA cleavage and host transcriptome modulation, not loss of viral small RNAs.

Conclusions:

• Drosha plays a critical role in the mammalian antiviral defense system.
• Drosha's cytoplasmic translocation is a conserved antiviral mechanism.
• Drosha combats viral infections through direct viral RNA cleavage and host transcriptome modulation.