Reovirus FAST proteins: virus-encoded cellular fusogens

• FAST proteins are a structurally and functionally distinct family of viral fusogens.
• These modular fusogens attack the membrane from both sides to induce membrane fusion.
• Pore expansion leading to syncytium formation may reflect a generalized cellular response to cell-cell fusion pores.
• Viral fusogens use more than one strategy to mediate membrane fusion.

Reovirus fusion-associated small transmembrane (FAST) proteins are the only known nonenveloped virus fusogens and are dedicated to inducing cell-to-cell, not virus–cell, membrane fusion. Numerous structural and functional attributes distinguish this novel family of viral fusogens from all enveloped virus membrane fusion proteins. Both families of viral fusogens play key roles in virus dissemination and pathogenicity, but employ different mechanisms to mediate membrane apposition and merger. However, convergence of these distinct families of viral membrane fusion proteins on common pathways needed for pore expansion and syncytium formation suggests syncytiogenesis represents a cellular response to the presence of cell–cell fusion pores. Together, FAST proteins and enveloped virus fusion proteins provide exceptional insights into the ubiquitous process of cell–cell membrane fusion and syncytium formation.