VSV-G: Structural and Functional Insights

Vesicular stomatitis virus glycoprotein G (VSV-G) is crucial in the viral life cycle, mediating entry into host cells and initiating infection. Understanding its structure and function is essential for developing antiviral strategies and enhancing gene therapy approaches.

Research on VSV-G has shed light on viral mechanisms and potential therapeutic applications. By exploring this glycoprotein, we can better understand how viruses exploit cellular machinery and identify targets for intervention.

Structural Organization And Glycosylation

The Vesicular stomatitis virus glycoprotein G (VSV-G) is a trimeric protein, composed of three identical subunits forming a functional unit. This structure is vital for its role in mediating viral entry. Each subunit consists of a large ectodomain, a single transmembrane domain, and a short cytoplasmic tail. The ectodomain binds to host cell receptors, essential for viral entry. The transmembrane domain anchors the protein in the viral envelope, while the cytoplasmic tail is involved in viral assembly and budding.

Glycosylation, the addition of carbohydrate groups, is a significant post-translational modification affecting VSV-G’s function and stability. This process occurs in the endoplasmic reticulum and Golgi apparatus, where enzymes add N-linked glycans to asparagine residues. Glycosylation influences proper protein folding, stability, and immune evasion. Studies have shown it can impact viral infectivity by affecting receptor interaction, as demonstrated in the Journal of Virology.

The structural integrity of VSV-G is maintained through disulfide bonds, crucial for stability under acidic conditions during endocytosis. This environment triggers conformational changes in VSV-G, facilitating the fusion of the viral envelope with the host cell membrane, allowing the viral genome to enter the host cell cytoplasm and initiate replication.

Membrane Fusion Mechanisms

Membrane fusion is a sophisticated mechanism instrumental in the life cycle of viruses like VSV. At the heart of this process is VSV glycoprotein G (VSV-G), which undergoes structural rearrangements to facilitate the merging of viral and host cell membranes. This fusion is initiated by VSV-G’s attachment to specific host cell receptors, priming the protein for conformational changes.

Once VSV-G binds to its receptor, the virus is internalized via endocytosis, encountering the acidic environment of the endosome. This low pH triggers fusogenic activity, exposing hydrophobic regions that insert into the host cell membrane, anchoring the viral particle and bringing the membranes close. The energy released during these changes helps overcome repulsive forces, facilitating merger.

The fusion process involves a hemifusion intermediate, where the outer leaflets of the viral and cellular membranes join, while inner leaflets remain distinct. This stage allows lipid reorganization, creating a fusion pore for the viral genome to pass into the host cell cytoplasm. The transition from hemifusion to full fusion is rapid, ensuring prompt delivery of the viral nucleocapsid for replication.

Particle Assembly And Maturation

The assembly of Vesicular stomatitis virus (VSV) particles involves viral and host cell components, resulting in infectious virions. The viral nucleocapsid interacts with the membrane-anchored VSV glycoprotein G (VSV-G), playing a significant role in budding and maturation. The nucleocapsid, a helical structure of viral RNA and nucleoproteins, associates with the viral matrix protein, bridging internal viral components and VSV-G in the host cell membrane.

The matrix protein drives budding, where viral components are enveloped by the host cell’s membrane. This process involves host cell machinery, including the ESCRT system, facilitating membrane scission and virion release. The selective incorporation of VSV-G ensures only properly folded glycoproteins are included, crucial for viral infectivity.

Post-budding, VSV particles undergo modifications enhancing stability and infectivity, including conformational adjustments in VSV-G. The structural integrity and proper orientation of VSV-G on the viral surface are fundamental for recognizing and binding to host cell receptors, a prerequisite for successful entry.

Interaction With Host Factors

The interaction between Vesicular stomatitis virus glycoprotein G (VSV-G) and host cellular factors showcases the virus’s adaptability in commandeering host machinery. VSV-G interacts with host cell receptors for viral entry and continues interfacing with host proteins to optimize viral replication and assembly. It modulates host intracellular trafficking pathways, ensuring efficient transport of viral particles to the cell surface for budding.

These interactions often involve manipulating host cell signaling pathways to create an environment conducive to viral replication. VSV-G can alter cellular processes such as apoptosis and autophagy, critical for cell survival. By suppressing apoptosis, VSV-G prolongs the infected cell’s lifespan, allowing maximal viral production. Simultaneously, modulation of autophagy pathways may aid in degrading cellular components, freeing resources for the virus.