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The axonal sorting activity of pseudorabies virus Us9 protein depends on the state of neuronal maturation
- Source :
- PLoS Pathogens, Vol 16, Iss 12, p e1008861 (2020), PLoS Pathogens
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- 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.<br />Author summary Viral pathogenesis often is age-dependent, with more severe outcomes for infected fetuses and neonates compared to adults. As neurons age and mature, dendrites and axons polarize with distinct functions that affect neurotropic virus replication and neuronal spread of infection. This study investigates how neuronal maturation of peripheral nervous system neurons, the site of alpha-herpesvirus life-long latency and reactivation, affects replication and neuronal spread of pseudorabies virus. Characterization of infected immature and mature primary cultures of superior cervical ganglionic neurons revealed significant differences in protein composition and cellular processes that affected the activity of Us9, a viral protein required for sorting virus particles into axons. We identified neuronal and viral proteins that interact with Us9 in immature and mature neurons. Among these, we demonstrate that SMPD4/nsMase3, a sphingomyelinase critical for membrane organization and neuronal function, regulates PRV neuronal spread by preventing capsid association with Us9-containing membranes, presenting a possible antiviral function.
- Subjects :
- Nervous system
Small interfering RNA
viruses
Viral pathogenesis
Pseudorabies
Virus Replication
medicine.disease_cause
Axonal Transport
Biochemistry
Viral Packaging
Rats, Sprague-Dawley
Nerve Fibers
0302 clinical medicine
Animal Cells
Biology (General)
Neuronal transport
Smad4 Protein
Neurons
0303 health sciences
biology
Intracellular Signaling Peptides and Proteins
Cell Differentiation
Lipids
Herpesvirus 1, Suid
Cell biology
Nucleic acids
Sphingomyelin Phosphodiesterase
medicine.anatomical_structure
Cell Processes
Host-Pathogen Interactions
Cellular Types
Neuronal Differentiation
Research Article
Neurite
QH301-705.5
Viral protein
Lipoproteins
Immunology
Microbiology
Virus
Viral Proteins
03 medical and health sciences
Developmental Neuroscience
Virology
Genetics
medicine
Animals
Non-coding RNA
Molecular Biology
030304 developmental biology
Neurotropic virus
Biology and Life Sciences
Cell Biology
RC581-607
biology.organism_classification
Axons
Viral Replication
Gene regulation
Rats
nervous system
Cellular Neuroscience
Axoplasmic transport
RNA
Parasitology
Gene expression
Immunologic diseases. Allergy
030217 neurology & neurosurgery
Neuroscience
Developmental Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens, Vol 16, Iss 12, p e1008861 (2020), PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....7f7facb7d901633ed1276fe18489985a