Transferrin Receptor Protein 1 Is an Entry Factor for Rabies Virus

Wang, Xinxin; Wen, Zhiyuan; Cao, Huizhen; Luo, Jie; Shuai, Lei; Wang, Chong; Ge, Jinying; Wang, Xijun; Bu, Zhigao; Wang, Jinliang

doi:10.1128/jvi.01612-22

Cited by 9 publications

(12 citation statements)

References 38 publications

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“…Our previous studies ( 26 ) combined with the above results demonstrate that TfR1, mGluR2, and RABV G interact with each other, which suggests that they might form a complex. To test this hypothesis, we performed a protein interaction competition assay.…”

Section: Resultssupporting

confidence: 56%

“…Interestingly, the lifetime of RABV endocytosis is also longer than that of classic TfR1 endocytosis ( 19 , 33 , 34 ). More importantly, in a recent study, we demonstrate that TfR1 is an entry factor for RABV ( 26 ). Therefore, we performed a co-immunoprecipitation assay using Flag-tagged mGluR2 protein (mGluR2-Flag) and Myc-tagged TfR1 protein (TfR1-Myc) in plasmid-transfected HEK293 cells to validate the interaction.…”

Section: Resultsmentioning

confidence: 53%

“…First, we examined which stage of RABV entry involves mGluR2. RNA interference (RNAi) assays were performed to determine whether mGluR2 affects the cell binding or internalization of RABV as previously described ( 26 ). Briefly, mGluR2-silenced HEK293 cells, N2a cells (a mouse neuroblastoma cell line), and control cells were incubated with a recombinant RABV ERA strain that expresses enhanced green florescence protein (ERA-EGFP), at 4°C for 1 h and then washed to remove unbound virus.…”

Section: Resultsmentioning

confidence: 99%

“…Most GPCRs are transported to an endocytic pathway after internalization ( 49 , 50 ). In our previous studies, we found that mGluR2 and TfR1 co-localize with RABV in early and late endosomes, respectively, and the interaction between mGluR2 or TfR1 and RABV G is not affected by acidic conditions ( 24 ) ( 26 ). These results indicate that mGluR2 likely cooperates with TfR1 to regulate RABV endosomal transport.…”

Section: Discussionmentioning

confidence: 96%

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Transferrin Receptor Protein 1 Cooperates with mGluR2 To Mediate the Internalization of Rabies Virus and SARS-CoV-2

Wang

Wen

Cao

et al. 2023

J Virol

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

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Transferrin Receptor Protein 1 Cooperates with mGluR2 To Mediate the Internalization of Rabies Virus and SARS-CoV-2

Wang

Wen

Cao

et al. 2023

J Virol

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“…Despite the advancement in rabies research which identified multiple cellular receptors for RABV (1,6-10), none of the previous studies have identified any of these receptors as indispensable for virus entry. To date, six cellular receptors have been identified to facilitate RABV entry such as nicotinic acetylcholine receptor α1 (nAChRα1) (11), neural cell adhesion molecule, (NCAM) (9), metabotropic glutamate receptor 2 (mGluR2) (7), integrin beta 1 (ITGB1) (1) and transferrin receptor protein 1 (10).…”

Section: Introductionmentioning

confidence: 99%

Structural and Mechanistic Usage and Preference of Human, Dog, and Bat Receptors by Rabies Virus

Khalifa,

Atasoy,

Rohaim

et al. 2023

Preprint

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Rabies is a lethal zoonotic viral disease causing approximately 59,000 human deaths annually. Recently, several cellular receptors for rabies virus (RABV) entry and internalization have been identified. However, none of these receptors have been demonstrated to be indispensable for RABV entry. Here we describe the RABV receptor preferencein vivo, utilizing a replication-competent vesicular stomatitis virus (VSV), in which the VSV surface glycoprotein was replaced with rabies virus glycoprotein. To investigate the specific role of RABV receptors in promoting RABV entry in non-permissive cell line, HaCaT cells were used as a cellular model refractory for RABV infection. Employing virus binding and quantification studies, we demonstrated that ITGB1 and mGluR2 are potential receptors for RABV entry and replication. Consequently, knockout (KO) cell lines corresponding to each of the ITGB1 and mGluR2 receptors were generated using CRISPR/Cas9 mediated knockout. Surprisingly, RABV was still able to enter and replicate in the generated KO cell lines, yet the replication and entry of RABV in KO cells lacking mGluR2 and ITGB1 were significantly reduced; respectively. These findings suggest that RABV utilize these receptors in series rather than sequentially. To test whether RABV utilizes similar receptor preference among human, dog, and bats, the A549, Pa-Br and MDCK cell lines that overexpress receptor orthologs from their respective species were infected with rVSV-dG-RABV-G-GFP and quantified for virus binding and released virus progeny. Our findings revealed that in human cells, ITGB1 increased virus entry, while nAChR enhanced virus replication. In bat cells, ectopic expression of nAChR allowed enhanced virus entry and internalization. While MDCK cells overexpressing ITGB1 enhanced the levels of virus entry and replication. Conclusively, our study, reveals the RABV distinct receptor preference, influenced by the underlying pathways that occur during the interaction between the virus and receptor in different cell lines. Additionally, it emphasizes the significance of host-specific factors in virus entry and replication.Graphical AbstractAuthor SummaryRabies is a fatal neurological disease, characterized by broad host range and tissue tropism. In accordance with the global goal of eliminating dog-mediated human rabies by 2030, studying the underlying mechanism of RABV entry across distinct species would enable adjustment of RABV control strategies. Owing to RABV wide tropism, multiple cellular receptors have been identified for RABV entry into host cells. Previous studies have proposed that some of RABV receptors could serve as promising candidates for development of antiviral drugs (1). From this perspective, we focused on elucidating RABV receptor preference for viral entry in human, dog, and bat cells. In addition to determining whether RABV utilizes these receptors in parallel or in series which would indicate the potential of the identified RABV cellular receptors as targets for antiviral drugs against rabies. Our results demonstrated varying receptor preference of RABV across species. In addition to revealing that none of RABV receptors solely, govern the broad host range of rabies, suggesting that RABV antiviral drugs targeting host cellular factors may not effectively inhibit RABV entry into cells, while antiviral drugs targeting virus glycoprotein may exhibit greater efficacy. Collectively, our study, contribute to providing mechanistic model for RABV entry in different species.

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Affinity Maturated Transferrin Receptor Apical Domain Blocks Machupo Virus Glycoprotein Binding

Sjöström,

Grill,

Ambrosetti

et al. 2023

Journal of Molecular Biology

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Transferrin Receptor Protein 1 Is an Entry Factor for Rabies Virus

Abstract: For most viruses, cell entry involves engagement with many distinct plasma membrane components, each of which is essential. After binding to its specific receptor(s), rabies virus (RABV) enters host cells through the process of clathrin-mediated endocytosis.

Cited by 9 publications

References 38 publications

Transferrin Receptor Protein 1 Cooperates with mGluR2 To Mediate the Internalization of Rabies Virus and SARS-CoV-2

Transferrin Receptor Protein 1 Cooperates with mGluR2 To Mediate the Internalization of Rabies Virus and SARS-CoV-2

Structural and Mechanistic Usage and Preference of Human, Dog, and Bat Receptors by Rabies Virus

Affinity Maturated Transferrin Receptor Apical Domain Blocks Machupo Virus Glycoprotein Binding

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