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<a href="http://doi.org/10.1186/1742-4690-7-93" target="_blank" rel="noreferrer noopener">http://doi.org/10.1186/1742-4690-7-93</a>
Pages
93–93
Volume
7
Dublin Core
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Title
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Misfolding of CasBrE SU is reversed by interactions with 4070A Env: implications for gammaretroviral neuropathogenesis.
Publisher
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Retrovirology
Date
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2010
2010-11
Subject
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Animals; Cell Line; env/*metabolism; Experimental/*virology; Gene Products; Helper Viruses/metabolism/pathogenicity/*physiology; Leukemia; Leukemia Virus; Mice; Motor Neuron Disease/*virology; Murine/metabolism/pathogenicity/*physiology; Neural Stem Cells/*virology; Protein Binding; Protein Folding; Protein Subunits/metabolism; Retroviridae Infections/*virology; Tumor Virus Infections/*virology; Virulence
Creator
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Li Ying; Lynch William P
Description
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BACKGROUND: CasBrE is a neurovirulent murine leukemia virus (MLV) capable of inducing paralytic disease with associated spongiform neurodegeneration. The neurovirulence of this virus has been genetically mapped to the surface expressed subunit (SU) of the env gene. However, CasBrE SU synthesized in the absence of the transmembrane subunit (TM) does not retain ecotropic receptor binding activity, indicating that folding of the receptor binding domain (RBD) requires this domain. Using a neural stem cell (NSC) based viral trans complementation approach to examine whether misfolded CasBrE SU retained neurovirulence, we observed CasBrE SU interaction with the "non-neurovirulent" amphotropic helper virus, 4070A which restored functional activity of CasBrE SU. RESULTS: Herein, we show that infection of NSCs expressing CasBrE SU with 4070A (CasES+4070A-NSCs) resulted in the redistribution of CasBrE SU from a strictly secreted product to include retention on the plasma membrane. Cell surface cross-linking analysis suggested that CasBrE SU membrane localization was due to interactions with 4070A Env. Viral particles produced from CasES+4070A-NSCS contained both CasBrE and 4070A gp70 Env proteins. These particles displayed ecotropic receptor-mediated infection, but were still 100-fold less efficient than CasE+4070A-NSC virus. Infectious center analysis showed CasBrE SU ecotropic transduction efficiencies approaching those of NSCs expressing full length CasBrE Env (CasE; SU+TM). In addition, CasBrE SU-4070A Env interactions resulted in robust ecotropic superinfection interference indicating near native intracellular SU interaction with its receptor, mCAT-1. CONCLUSIONS: In this report we provided evidence that 4070A Env and CasBrE SU physically interact within NSCs leading to CasBrE SU retention on the plasma membrane, incorporation into viral particles, restoration of mCAT-1 binding, and capacity for initiation of TM-mediated fusion events. Thus, heterotropic Env-SU interactions facilitates CasBrE SU folding events that restore Env activity. These findings are consistent with the idea that one protein conformation acts as a folding scaffold or nucleus for a second protein of similar primary structure, a process reminiscent of prion formation. The implication is that template-based protein folding may represent an inherent feature of neuropathogenic proteins that extends to retroviral Envs.
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<a href="http://doi.org/10.1186/1742-4690-7-93" target="_blank" rel="noreferrer noopener">10.1186/1742-4690-7-93</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2010
Animals
Cell Line
Department of Integrative Medical Sciences
env/*metabolism
Experimental/*virology
Gene Products
Helper Viruses/metabolism/pathogenicity/*physiology
Leukemia
Leukemia Virus
Li Ying
Lynch William P
Mice
Motor Neuron Disease/*virology
Murine/metabolism/pathogenicity/*physiology
NEOMED College of Medicine
Neural Stem Cells/*virology
Protein Binding
Protein Folding
Protein Subunits/metabolism
Retroviridae Infections/*virology
Retrovirology
Tumor Virus Infections/*virology
Virulence