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

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 heathy host, it can spread within the neuronal circuitry in compromised individuals leading to adverse health consequences. Pseudorabies virus (PRV) an alpha-herpesvirus, requires the viral protein Us9 for sorting virus particles into axons. It does so by mediating an interaction of virus particles with neuronal transport machinery. Us9-mediated axonal sorting also depends on the state of neuronal maturation as the proteome composition changes with neuronal development of dendrites and axons. Immature superior cervical ganglia (SCGs) have rudimentary neurites that lack markers of mature dendrites or axons. Immature SCGs can be infected by PRV, but show markedly reduced Us9-dependent sorting into neurites. Mature SCGs abundantly express a variety of proteins characteristic of vesicle-transport machinery. Proteomics studies identified several novel Us9-associated neuronal proteins with potential roles in the regulation of axonal sorting and subsequent anterograde spread of virus particles in axons. For example, we found that SMPD4/n-sMase3, a sphingomyelinase abundant in lipid-rafts, associates with Us9 and is a negative regulator of axonal mediated spread of PRV, a potential novel antiviral function.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat)

SUBMITTER: Joel Federspiel

LAB HEAD: Ileana Cristea

PROVIDER: PXD017822 | Pride | 2021-01-04

REPOSITORIES: Pride

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

Tanneti Nikhila S NS Federspiel Joel D JD Cristea Ileana M IM Enquist Lynn W LW

PLoS pathogens 20201228 12

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 med ...[more]

PMID: 33370419

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Project description:Spinocerebellar ataxia type 3 (SCA3/MJD) has a polyQ etiology but, the current knowledge on molecular processes and proteins involved in pathogenesis is insufficient. Due to its proteolytic function, Ataxin-3 can influence other proteins, yet the global picture of crucial proteins and pathways in SCA3 was not investigated previously. Here, we explored molecular SCA3 mechanism by interdisciplinary research paradigm combining SCA3 knock-in model, behavior, MRI, brain proteomics, precise axonal proteomics, neuronal energy recordings, labeling of vesicles, and inclusions and focusing in axonal compartment. Using the global proteomics, we found dysregulation of protein homeostasis over the entire disease progression. The early SCA3 phase was associated with reduced body weight gain, the presence of the number of dysregulated proteins related to metabolism and mitochondria, and an altered profile of oxygen consumption rate in neurons. Moreover, the early phase presented alterations of protein metabolism, cytoskeletal architecture, axonal and synaptic proteins. Protein dysregulations indicated that the compartment involved in SCA3 pathogenesis next to the mitochondria are also neuronal processes and axons in particular. To confirm that the axon is one of the central compartments in SCA3 pathogenesis, we performed targeted proteomics on axons and somatodendritic compartments. We revealed highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport and mitochondria was decreased. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of protein synthetic machinery in axons.

Dataset Information

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

Publications

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

Similar Datasets

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