1.G.7 The Reovirus FAST Fusion Protein (R-FAST) Family
The FAST proteins are a unique family of virus-encoded cell-cell membrane fusion proteins. In the absence of a cleavable N-terminal signal peptide, a single-pass transmembrane domain (TMD) functions as a reverse signal-anchor to direct the FAST proteins into the plasma membrane in an N(exo)/C(cyt) topology. There is little information available on the role of the FAST protein TMD in the cell-cell membrane fusion reaction. Clancy and Duncan (2009) showed that in the absence of conservation in the length or primary amino acid sequence, the p14 TMD can be functionally exchanged with the TMDs of the p10 and p15 FAST proteins. This is not the case for chimeric p14 proteins containing the TMDs of two different enveloped viral fusion proteins or a cellular membrane protein; such chimeric proteins were defective for both pore formation and syncytiogenesis. TMD structural features that are conserved within members of the FAST protein family presumably play direct roles in the fusion reaction. Molecular modeling suggests that the funnel-shaped architecture of the FAST protein TMDs may represent such a conserved structural and functional motif. Interestingly, although heterologous TMDs exert diverse influences on the trafficking of the p14 FAST protein, these TMDs are capable of functioning as reverse signal-anchor sequences to direct p14 into lipid rafts in the correct membrane topology.
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 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 insight into the process of cell-cell membrane fusion and syncytium formation (Ciechonska and Duncan 2014).