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PLoS Pathog. 2020 Jan 29;16(1):e1007985. doi: 10.1371/journal.ppat.1007985. eCollection 2020 Jan.

A kinesin-3 recruitment complex facilitates axonal sorting of enveloped alpha herpesvirus capsids.

Author information

1
Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America.
2
Center for Immunotherapy, Vaccines, and Virotherapy, Biodesign Institute & School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America.
3
University of Washington, Seattle, Washington, United States of America.
4
Department of Physics and Astronomy, University of Utah, Salt Lake City, Utah, United States of America.

Abstract

Axonal sorting, the controlled passage of specific cargoes from the cell soma into the axon compartment, is critical for establishing and maintaining the polarity of mature neurons. To delineate axonal sorting events, we took advantage of two neuroinvasive alpha-herpesviruses. Human herpes simplex virus 1 (HSV-1) and pseudorabies virus of swine (PRV; suid herpesvirus 1) have evolved as robust cargo of axonal sorting and transport mechanisms. For efficient axonal sorting and subsequent egress from axons and presynaptic termini, progeny capsids depend on three viral membrane proteins (Us7 (gI), Us8 (gE), and Us9), which engage axon-directed kinesin motors. We present evidence that Us7-9 of the veterinary pathogen pseudorabies virus (PRV) form a tripartite complex to recruit Kif1a, a kinesin-3 motor. Based on multi-channel super-resolution and live TIRF microscopy, complex formation and motor recruitment occurs at the trans-Golgi network. Subsequently, progeny virus particles enter axons as enveloped capsids in a transport vesicle. Artificial recruitment of Kif1a using a drug-inducible heterodimerization system was sufficient to rescue axonal sorting and anterograde spread of PRV mutants devoid of Us7-9. Importantly, biophysical evidence suggests that Us9 is able to increase the velocity of Kif1a, a previously undescribed phenomenon. In addition to elucidating mechanisms governing axonal sorting, our results provide further insight into the composition of neuronal transport systems used by alpha-herpesviruses, which will be critical for both inhibiting the spread of infection and the safety of herpesvirus-based oncolytic therapies.

Conflict of interest statement

The authors have declared that no competing interests exist.

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