Selective targeting and clustering of phosphatidylserine lipids by RSV M protein is critical for virus particle production
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Updated: Jul 14, 2025
Generation, Amplification, and Titration of Recombinant Respiratory Syncytial Viruses
Published on: April 4, 2019
Jitendriya Swain1, Maxime Bierre2, Laura Veyrié1
1Virology and Molecular Immunology Unit (VIM), Animal Health Department, INRAE, IRIM, Montpellier, France.
Insights
Respiratory syncytial virus (RSV) matrix (M) proteins selectively bind to phosphatidylserine (PS) lipids on the host cell plasma membrane. This M-PS interaction drives viral assembly and clustering, offering new targets for antiviral therapies.
Area of Science:
- Virology
- Structural Biology
- Biochemistry
Background:
- Human respiratory syncytial virus (RSV) is a major cause of infant respiratory illness and a significant global health concern.
- RSV assembly involves the matrix (M) protein interacting with host cell plasma membrane lipids, but the specific lipids and mechanisms remain unclear.
- Understanding M protein-lipid interactions is crucial for developing novel antiviral strategies and vaccines against RSV.
Purpose of the Study:
- To elucidate the specific host cell membrane lipids that interact with the RSV M protein during viral assembly.
- To investigate the mechanism by which M protein binding to lipids influences viral particle formation.
- To determine the role of phosphatidylserine (PS) in M protein-mediated viral assembly.
Main Methods:
- In vitro lipid-binding assays using purified RSV M protein and various lipid compositions.
- Analysis of M protein oligomerization and its effect on lipid clustering.
- Investigation of M protein interaction with lipids independent of the fusion (F) glycoprotein cytoplasmic tail.
Main Results:
- RSV M protein selectively binds to phosphatidylserine (PS) lipids at the plasma membrane.
- M protein dimer binding to PS promotes M protein oligomerization and subsequent PS clustering.
- Other negatively charged lipids (e.g., PI(4,5)P2) and cholesterol do not enhance or negatively affect M protein-lipid interactions.
- Initial M protein binding to PS is independent of the F glycoprotein cytoplasmic tail.
Conclusions:
- RSV M protein directly interacts with host cell PS lipids through electrostatic interactions.
- M protein oligomerization induced by PS binding is a key event in viral assembly.
- Targeting the M protein-PS interaction presents a promising strategy for developing new anti-RSV therapeutics.
Abstract:
Human respiratory syncytial virus (RSV) is the leading cause of infantile bronchiolitis in the developed world and of childhood deaths in resource-poor settings. The elderly and the immunosuppressed are also affected. It is a major unmet target for vaccines and antiviral drugs. RSV assembles and buds from the host cell plasma membrane by forming infectious viral particles which are mostly filamentous. A key interaction during RSV assembly is the interaction of the matrix (M) protein with cell plasma membrane lipids forming a layer at assembly sites. Although the structure of RSV M protein dimer is known, it is unclear how the viral M proteins interact with cell membrane lipids, and with which one, to promote viral assembly. Here, we demonstrate that M proteins are able to cluster at the plasma membrane by selectively binding with phosphatidylserine (PS). Our in vitro studies suggest that M binds PS lipid as a dimer and upon M oligomerization, PS clustering is observed. In contrast, the presence of other negatively charged lipids like PI(4, 5)P2 does not enhance M binding beyond control zwitterionic lipids, while cholesterol negatively affects M interaction with membrane lipids. Moreover, we show that the initial binding of the RSV M protein with PS lipids is independent of the cytoplasmic tail of the fusion (F) glycoprotein (FCT). Here, we highlight that M binding on membranes occurs directly through PS lipids, this interaction is electrostatic in nature, and M oligomerization generates PS clusters.
