The Reovirus Fusion-Associated Small Transmembrane (FAST) Proteins: Virus-Encoded Cellular Fusogens

Bioinformatics of Recent Aqua- and Orthoreovirus Isolates from Fish: Evolutionary Gain or Loss of FAST and Fiber Proteins and Taxonomic Implications

“…The C-terminal region of NS41 is also enriched in Arg and Pro residues, similarly to the AqRV-A FAST proteins [5], [24], and this region has predicted propensity for intrinsic disorder. Importantly, however, NS41 is 2–3 times larger than any other known FAST protein, and the locations of its predicted TMDs are inconsistent with FAST-protein membrane topology [18].…”

“…We therefore used bioinformatics approaches to search for FAST-protein homologs encoded by these viruses. FAST proteins share several common features, including their small size (<200 aa), a single transmembrane domain (TMD) located <40 aa from the N terminus, a cluster of basic residues on the C-terminal side of the TMD, sites for modification by fatty acids (N-terminal myristoylation, or palmitoylation on membrane-proximal Cys residues), a short amphipathic or hydrophobic motif that can be located on either side of the TMD, and C-terminal cytosolic endodomains with predicted propensity for intrinsic disorder [18].…”

“…One is the outer-fiber protein present in most orthoreoviruses, which anchors atop the core-turret protein at the icosahedral fivefold axes of virions [6], [10], [11] and mediates attachment to cell-surface receptors [12]–[16]. The other is the NS fusion-associated small transmembrane (FAST) protein of aquareoviruses and most orthoreoviruses [17], [18], which promotes cell-to-cell spread by fostering syncytium formation and release of progeny virions via syncytium-induced cytopathic effects [19], [20] (Tables 1, 2, and S1). In members of approved Orthoreovirus species, the single genome segment not shared by aquareoviruses is the one that encodes either the outer-fiber protein (in Mammalian orthoreovirus isolates [MRVs]) or the NS-FAST protein (in the Baboon orthoreovirus isolate [BRV]), or both (in Avian orthoreovirus , Nelson Bay orthoreovirus , and Reptilian orthoreovirus isolates [ARVs, NBVs, and RRVs, respectively]) [21]–[23].…”

Membrane Perturbation-Associated Ca 2+ Signaling and Incoming Genome Sensing Are Required for the Host Response to Low-Level Enveloped Virus Particle Entry

“…While one explanation is that the p14 protein is sensed by an unknown receptor, it is unlikely that p14 serves as a PAMP due to its size and structural dissimilarity with enveloped virus fusion proteins (54). It is intriguing that while we routinely detect ISG and antiviral state induction in response to envelope virus particle entry within 6 to 8 h in fibroblasts, the response to p14-lipoprotein complexes requires ϳ12 h, despite induction of the same subset of ISGs (11,21).…”

A Compact, Multifunctional Fusion Module Directs Cholesterol-Dependent Homomultimerization and Syncytiogenic Efficiency of Reovirus p10 FAST Proteins

“…The FAST proteins share no identifiable sequence similarity with each other, or with any other known membrane fusion protein, and each possesses a unique repertoire and arrangement of functional motifs. Defining attributes of family members include their small size (95–198 amino acids), presence of a single-pass transmembrane domain (TMD) with N exoplasmic /C endoplasmic membrane topology resulting in ectodomains of <40 residues, sites for fatty-acid modification (N-terminal myristoylation or palmitoylation of membrane proximal Cys residues), a cluster of membrane-proximal basic residues on the cytoplasmic side of the TMD, a short hydrophobic or amphipathic motif that can be located on either side of the TMD, and an intrinsically disordered cytoplasmic tail [25], [27], [31]–[33]. Determining how these motifs function in a coordinated manner to mediate membrane fusion is critical to our understanding of how these unusual viral fusion proteins mediate syncytiogenesis, and how this process influences viral pathogenesis.…”