Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release

Area of Science:

• Virology
• Cell Biology
• Molecular Biology

Background:

• Enterovirus D68 (EV-D68) is a virus causing respiratory illness and, rarely, acute flaccid myelitis.
• EV-D68 benefits from nonselective autophagy during infection.
• The role of selective autophagy, specifically mitophagy, in EV-D68 infection is not fully understood.

Purpose of the Study:

• To investigate the role of mitophagy in EV-D68 infection.
• To determine how EV-D68 interacts with mitochondrial dynamics and autophagy pathways.
• To elucidate the mechanism of EV-D68 release from host cells.

Main Methods:

• Analysis of viral protease activity on mitochondrial proteins.
• Microscopy to observe mitochondrial network fragmentation and mitophagosome formation.
• Assessment of mitophagy markers, including mitochondrial membrane potential and Parkin translocation.
• Experiments involving Mitofusin 2 depletion or overexpression to study viral release.

Main Results:

• The EV-D68 3C protease cleaves Mitofusin 2, leading to mitochondrial fragmentation.
• Mitophagosome formation occurs during EV-D68 infection, but mitochondrial degradation is inhibited.
• Mitofusin 2 cleavage and subsequent mitophagosome induction are crucial for nonlytic EV-D68 release.
• Reducing Mitofusin 2 levels or using a cleavage-resistant mutant impairs viral release without affecting intracellular viral titers.

Conclusions:

• EV-D68 induces mitophagosomes as a mechanism for nonlytic release of virions.
• Mitofusin 2 cleavage by EV-D68 protease is a key step in this process.
• Targeting this pathway could offer strategies to control EV-D68 spread.