Widespread remodeling of the m⁶A RNA-modification landscape by a viral regulator of RNA processing and export

Area of Science:

• Molecular Biology
• Virology
• Epigenetics

Background:

• N6-methyladenosine (m6A) is a crucial RNA modification impacting RNA processing, stability, and function.
• The m6A methyltransferase complex (METTL3, METTL14, WTAP) is essential for methylation during pre-mRNA synthesis.
• Herpes simplex virus type 1 (HSV-1) infection suppresses host gene expression to hijack cellular machinery.

Purpose of the Study:

• To investigate whether HSV-1 manipulates the host m6A RNA modification pathway.
• To understand the impact of HSV-1 infection on the localization and function of the m6A machinery.

Main Methods:

• Primary fibroblasts were infected with HSV-1.
• Immunofluorescence microscopy was used to track the redistribution of m6A machinery components (METTL3, METTL14, WTAP, YTHDC1, ALKBH5).
• Small interfering RNA (siRNA) was used to inactivate the m6A methyltransferase.

Main Results:

• HSV-1 infection caused a significant redistribution of nuclear m6A machinery components.
• METTL3 and METTL14 dispersed to the cytoplasm, while WTAP remained nuclear.
• ICP27, a viral regulator, was required for these redistribution events and nucleocytoplasmic export of viral late mRNAs.
• m6A installation on host and viral mRNAs was reduced during infection.
• siRNA-mediated inactivation of m6A methyltransferase initially reduced viral gene expression.

Conclusions:

• HSV-1 actively orchestrates the redistribution of the host m6A machinery during infection.
• This viral strategy, dependent on ICP27, leads to reduced m6A modification of host and viral RNAs.
• The subversion of the m6A pathway by HSV-1 contributes to the suppression of host gene expression and facilitates viral replication.