METTL3 regulates PRRSV replication by suppressing interferon beta through autophagy-mediated IKKε degradation

Area of Science:

• Virology
• Immunology
• Epigenetics

Background:

• Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses in the swine industry.
• PRRSV's immune evasion mechanisms are complex and hinder vaccine development.
• The role of METTL3-mediated RNA methylation in PRRSV infection was previously unclear.

Purpose of the Study:

• To elucidate the function of METTL3 in PRRSV infection.
• To investigate the molecular mechanisms by which METTL3 influences the host immune response to PRRSV.
• To identify potential therapeutic targets for PRRSV control.

Main Methods:

• Analysis of METTL3 expression and subcellular localization during PRRSV infection.
• Investigation of METTL3's effect on PRRSV replication and type I interferon production.
• Identification of METTL3 interacting proteins and downstream targets using molecular biology techniques.
• Assessment of autophagy pathway involvement in METTL3-mediated protein degradation.

Main Results:

• PRRSV infection increases METTL3 expression and alters its localization.
• METTL3 overexpression enhances PRRSV replication, while METTL3 deficiency suppresses it.
• METTL3 promotes the degradation of IκB kinase-ε (IKKε) via SQSTM1-dependent autophagy.
• METTL3-mediated m⁶A modification of SQSTM1 enhances autophagy, contributing to IKKε degradation and suppressed type I interferon production.

Conclusions:

• METTL3 facilitates PRRSV replication by suppressing antiviral innate immunity.
• METTL3 targets IKKε for degradation, inhibiting type I interferon production.
• METTL3-mediated epigenetic regulation of autophagy is a key mechanism for PRRSV immune evasion.
• METTL3 presents a potential therapeutic target for controlling PRRSV infections.