Distinct pathways utilized by METTL3 to regulate antiviral innate immune response

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Methyltransferase-like 3 (METTL3) is central to N-methyladenosine (m6A) RNA modifications.
• METTL3's role in innate immunity and antiviral responses requires further elucidation.
• Understanding METTL3's broader functions is critical for developing novel antiviral strategies.

Purpose of the Study:

• To investigate the regulation of METTL3 expression during Enterovirus 71 (EV71) infection.
• To determine the mechanisms by which METTL3 influences antiviral immune responses.
• To explore both m6A-dependent and m6A-independent roles of METTL3 in immunity.

Main Methods:

• Analysis of METTL3 expression in EV71-infected cells (Vero and RD).
• Investigation of METTL3's impact on viral RNA recognition by RIG-I.
• Examination of METTL3 interactions with DDX3X and its effect on ubiquitination.
• Assessment of m6A-dependent and -independent regulatory pathways.

Main Results:

• EV71 infection upregulated METTL3 expression through transcriptional and post-translational modifications.
• METTL3 inhibited viral RNA recognition by RIG-I via m6A modification.
• METTL3's non-catalytic function stabilized DDX3X by preventing its ubiquitination, inhibiting immune responses.
• Both m6A-dependent and -independent mechanisms contribute to METTL3's immune regulation.

Conclusions:

• METTL3 plays a dual role in regulating antiviral immunity, involving both m6A deposition and m6A-independent protein interactions.
• The study reveals a novel m6A-independent pathway for METTL3-mediated immune regulation.
• METTL3 presents a promising target for developing new antiviral therapies.