The axonal sorting activity of pseudorabies virus Us9 protein depends on the state of neuronal maturation.

TitleThe axonal sorting activity of pseudorabies virus Us9 protein depends on the state of neuronal maturation.
Publication TypeJournal Article
Year of Publication2020
AuthorsTanneti, NS, Federspiel, JD, Cristea, IM, Enquist, LW
JournalPLoS Pathog
Volume16
Issue12
Paginatione1008861
Date Published2020 12
ISSN1553-7374
KeywordsAnimals, Herpesvirus 1, Suid, Host-Pathogen Interactions, Intracellular Signaling Peptides and Proteins, Lipoproteins, Neurons, Pseudorabies, Rats, Rats, Sprague-Dawley, Smad4 Protein, Sphingomyelin Phosphodiesterase, Viral Proteins, Virus Replication
Abstract

<p>Alpha-herpesviruses establish a life-long infection in the nervous system of the affected host; while this infection is restricted to peripheral neurons in a healthy host, the reactivated virus can spread within the neuronal circuitry, such as to the brain, in compromised individuals and lead to adverse health outcomes. Pseudorabies virus (PRV), an alpha-herpesvirus, requires the viral protein Us9 to sort virus particles into axons and facilitate neuronal spread. Us9 sorts virus particles by mediating the interaction of virus particles with neuronal transport machinery. Here, we report that Us9-mediated regulation of axonal sorting also depends on the state of neuronal maturation. Specifically, the development of dendrites and axons is accompanied with proteomic changes that influence neuronal processes. Immature superior cervical ganglionic neurons (SCGs) have rudimentary neurites that lack markers of mature axons. Immature SCGs can be infected by PRV, but they show markedly reduced Us9-dependent regulation of sorting, and increased Us9-independent transport of particles into neurites. Mature SCGs have relatively higher abundances of proteins characteristic of vesicle-transport machinery. We also identify Us9-associated neuronal proteins that can contribute to axonal sorting and subsequent anterograde spread of virus particles in axons. We show that SMPD4/nsMase3, a sphingomyelinase abundant in lipid-rafts, associates with Us9 and is a negative regulator of PRV sorting into axons and neuronal spread, a potential antiviral function.</p>

DOI10.1371/journal.ppat.1008861
Alternate JournalPLoS Pathog
PubMed ID33370419
PubMed Central IDPMC7794026
Grant ListR01 GM114141 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States