Abstract
The reovirus fusion-associated small transmembrane (FAST) proteins function as virus-encoded cellular fusogens, mediating efficient cell–cell rather than virus–cell membrane fusion. With ectodomains of only ∼20–40 residues, it is unclear how such diminutive viral fusion proteins mediate the initial stages (i.e. membrane contact and close membrane apposition) of the fusion reaction that precede actual membrane merger. We now show that the FAST proteins lack specific receptor-binding activity, and in their natural biological context of promoting cell–cell fusion, rely on cadherins to promote close membrane apposition. The FAST proteins, however, are not specifically reliant on cadherin engagement to mediate membrane apposition as indicated by their ability to efficiently utilize other adhesins in the fusion reaction. Results further indicate that surrogate adhesion proteins that bridge membranes as close as 13 nm apart enhance FAST protein-induced cell–cell fusion, but active actin remodelling is required for maximal fusion activity. The FAST proteins are the first example of membrane fusion proteins that have specifically evolved to function as opportunistic fusogens, designed to exploit and convert naturally occurring adhesion sites into fusion sites. The capacity of surrogate, non-cognate adhesins and active actin remodelling to enhance the cell–cell fusion activity of the FAST proteins are features perfectly suited to the structural and functional evolution of these fusogens as the minimal fusion component of a virus-encoded cellular fusion machine. These results also provide a basis for reconciling the rudimentary structure of the FAST proteins with their capacity to fuse cellular membranes.
Highlights
By nature of their route of entry into cells, enveloped viruses possess proteins dedicated to the regulation and execution of membrane fusion between the viral envelope and target cell membrane
The reovirus Fusion-Associated Small Transmembrane (FAST) proteins are the only example of virus-encoded cellular fusogens, designed to mediate cell–cell rather than virus–cell membrane fusion
In view of their small size, it was unclear if, or how, the fusion-associated small transmembrane (FAST) proteins are responsible for promoting the membrane attachment and close apposition stages of the fusion reaction
Summary
By nature of their route of entry into cells, enveloped viruses possess proteins dedicated to the regulation and execution of membrane fusion between the viral envelope and target cell membrane. The emerging paradigm predicts that triggered rearrangements in the fusion protein complex result in exposure and membrane insertion of a fusion peptide, followed by folding back of the extended structure and hairpin formation that presumably drives membrane apposition and merger [10,11]. A slightly different situation occurs in the alphaviruses, where the receptor binding E2 glycoprotein initially forms a heterodimer with the E1 membrane fusion polypeptide; a low pH trigger and insertion of the fusion peptide into target membranes converts E1 to a functional, homotrimeric fusion protein [18]. Even the herpesviruses and the majority of the paramyxoviruses, that utilize separate multimeric proteins for the membrane contact and membrane merger steps of fusion reaction, couple membrane binding to membrane fusion via transient lateral interactions that are believed to be involved in triggering the structural transition of the fusion protein [8,19]
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