Not your usual tRNA synthetase: hWARS serves as an enterovirus entry factor
Stanley Perlman, Tom Gallagher
Stanley Perlman, Tom Gallagher
Published October 15, 2018
Citation Information: J Clin Invest. 2018;128(11):4767-4769. https://doi.org/10.1172/JCI124582.
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Commentary

Not your usual tRNA synthetase: hWARS serves as an enterovirus entry factor

Abstract

Enteroviruses, including subtype EV-A71, infect the brain, liver, heart, and other organs, causing a myriad of human diseases. This spectrum of disease is thought to be due, in part, to differential binding to host cells, and additional knowledge of enterovirus cell entry is essential for therapeutic development. In this issue of the JCI, Yeung et al. provide evidence of a novel EV-A71 entry factor, a host-produced tryptophan tRNA synthetase (hWARS), that facilitates entry of multiple subtypes of enteroviruses. hWARS is a cytoplasmic enzyme that is essential for translation but also upregulated and secreted during inflammatory processes. The results of this study support the notion of secreted hWARS as an unconventional virus entry factor that raises interesting questions about mechanisms by which inflammation and a tRNA synthetase facilitate viral pathogenesis.

Authors

Stanley Perlman, Tom Gallagher

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Figure 1

Possible mechanisms to explain surface expression of a tRNA synthetase.

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Possible mechanisms to explain surface expression of a tRNA synthetase. ...
hWARS is typically expressed as a cytoplasmic protein (i); however, in this issue, Yeung et al. demonstrate that hWARS is secreted in response to IFN-γ stimulation, and the secreted form binds to and promotes entry of EV-A71. In Model 1, hWARS is directly transported and anchored to the plasma membrane by an unknown mechanism (ii). EV-A71 then enters cells by binding to hWARS on the surface (iii). In Model 2, hWARS is enclosed in a vesicle in the cell (iv) and is released into the extracellular medium, probably after fusion of the vesicle with the cell membrane (v). Free hWARS (iv) then binds to virus, with the complex entering cells via binding to MD2-TLR4 or another surface membrane–bound protein. At this point, the entire EV-A71–hWARS-MD2-TLR4 enters the cell via endocytosis, prior to RNA delivery into the cytoplasm.