Rabies virus-induced membrane fusion pathway.

Area of Science:

• Virology
• Membrane Biophysics
• Molecular Biology

Background:

• Rabies virus fusion with host membranes is pH-dependent and mediated by the viral glycoprotein (G).
• Understanding the molecular mechanisms of viral fusion is crucial for developing antiviral strategies.

Purpose of the Study:

• To investigate the role of exogenous lipids with varying molecular shapes in the rabies virus-induced membrane fusion pathway.
• To elucidate the rate-limiting steps and intermediate complexes involved in rabies virus fusion.

Main Methods:

• Studying the effects of lysophosphatidylcholines (LPCs) with different alkyl chain lengths on viral fusion.
• Analyzing fusion kinetics and intermediate states under varying lipid compositions and conditions.
• Characterizing the cold-stabilized prefusion complex.

Main Results:

• Inverted cone-shaped LPCs inhibited fusion post-fusion peptide insertion, with shorter chains being more potent inhibitors.
• Short-chain LPCs, when translocated to the inner leaflet, reduced lag time and accelerated fusion kinetics under suboptimal conditions.
• Evidence suggests the rate-limiting step is fusion pore formation within a hemifusion diaphragm.
• The dynamic nature of the cold-stabilized prefusion complex was characterized, showing potential for lipid organization reversal.

Conclusions:

• Lipid shape and dynamics play a critical role in regulating rabies virus fusion.
• Fusion pore formation is a key rate-limiting step in the rabies virus-membrane fusion process.
• The prefusion complex is a dynamic intermediate that can potentially reverse its lipid organization.