Involvement of VCP/UFD1/Nucleolin in the viral entry of Enterovirus A species

Yan, Jian; Wang, Meng; Wang, Min; Dun, Ying; Zhu, Liuyao; Yi, Zhigang; Zhang, Shuye

doi:10.1016/j.virusres.2020.197974

Cited by 9 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Depletion of UFD1 did not affect virus entry but resulted in significant inhibition of virus replication and egress, validating its role as an essential host factor for JEV replication. A role of UFD1 for EV71 entry has been described in an siRNA-based screen of 31 VCP cofactors (56). The VCP-UFD-NPL4 complex has also been shown to negatively regulate type I interferon signaling through proteasomal degradation of RIG-I in the context of VSV infection (57).…”

Section: Discussionmentioning

confidence: 99%

Valosin-Containing Protein/p97 Plays Critical Roles in the Japanese Encephalitis Virus Life Cycle

Sehrawat

Khasa

Deb

et al. 2021

J Virol

View full text Add to dashboard Cite

Host factors provide critical support for every aspect of the virus life cycle. We recently identified the valosin-containing protein (VCP)/p97, an abundant cellular ATPase with diverse cellular functions, as a host factor important for Japanese encephalitis virus (JEV) replication. In cultured cells, using siRNA-mediated protein depletion and pharmacological inhibitors, we show that VCP is crucial for replication of three flaviviruses: JEV, Dengue, and West Nile viruses. An FDA-approved VCP inhibitor, CB-5083, extended survival of mice in the animal model of JEV infection. While VCP depletion did not inhibit JEV attachment on cells, it delayed capsid degradation, potentially through the entrapment of the endocytosed virus in clathrin-coated vesicles (CCVs). Early during infection, VCP-depleted cells showed an increased colocalization of JEV capsid with clathrin, and also higher viral RNA levels in purified CCVs. We show that VCP interacts with the JEV nonstructural protein NS5 and is an essential component of the virus replication complex. The depletion of the major VCP cofactor UFD-1 also significantly inhibited JEV replication. Mechanistically, thus, VCP affected two crucial steps of the JEV life cycle – nucleocapsid release and RNA replication. Our study establishes VCP as a common host factor with a broad antiviral potential against flaviviruses. Importance JEV is the leading cause of viral encephalitis epidemics in South-east Asia, affecting majorly children with high morbidity and mortality. Identification of host factors is thus essential for the rational design of anti-virals that are urgently need as therapeutics. Here we have identified the VCP protein as one such host-factor. This protein is highly abundant in cells and engages in diverse functions and cellular pathways by its ability to interact with different co-factors. Using siRNA mediated protein knockdown, we show that this protein is essential for release of the viral RNA into the cell so that it can initiate replication. The protein plays a second crucial role for the formation of the JEV replication complex. FDA-approved drugs targeting VCP show enhanced mouse survival in JE model of disease, suggesting that this could be a druggable target for flavivirus infections.

show abstract

Section: Discussionmentioning

confidence: 99%

Valosin-Containing Protein/p97 Plays Critical Roles in the Japanese Encephalitis Virus Life Cycle

Sehrawat

Khasa

Deb

et al. 2021

J Virol

View full text Add to dashboard Cite

show abstract

“…Cell surface NCL plays an important role in viral internalization and entry and is involved in EV71 entry via its interactions with the VP1 capsid of this virus ( 36 , 48 ). Influenza A virus hemagglutinin interacts with cell surface NCL, facilitating viral internalization and entry ( 49 ) while the RHDV capsid protein interacts with NCL to facilitate viral internalization via clathrin-dependent endocytosis ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Seneca Valley Virus 3C ^pro Mediates Cleavage and Redistribution of Nucleolin To Facilitate Viral Replication

et al. 2022

View full text Add to dashboard Cite

show abstract

“…For virus-binding experiments, cells were washed three times with ice-cold PBS and then the total RNA of infected cells was purified using a FastPure Cell/Tissue Total RNA Isolation Kit (Vazyme, Nanjing, China). For the virus internalization assay, experiments were performed as described previously for WNV, AAV and EMCV [32,33]. In brief, after binding, the virus inoculum was removed, and pre-warmed DMEM was added to the plate.…”

Section: Viral Binding and Internalization Assays By Qpcrmentioning

confidence: 99%

Identification of Critical Amino Acids of Coxsackievirus A10 Associated with Cell Tropism and Viral RNA Release during Uncoating

Pei,

Liu,

Yang

et al. 2023

Viruses

View full text Add to dashboard Cite

Coxsackievirus A10 (CV-A10) is a prevailing causative agent of hand–foot–mouth disease, necessitating the isolation and adaptation of appropriate strains in cells allowed for human vaccine development. In this study, amino acid sequences of CV-A10 strains with different cell tropism on RD and Vero cells were compared. Various amino acids on the structural and non-structural proteins related to cell tropism were identified. The reverse genetic systems of several CV-A10 strains with RD+/Vero− and RD+/Vero+ cell tropism were developed, and a set of CV-A10 recombinants were produced. The binding, entry, uncoating, and proliferation steps in the life cycle of these viruses were evaluated. P1 replacement of CV-A10 strains with different cell tropism revealed the pivotal role of the structural proteins in cell tropism. Further, seven amino acid substitutions in VP2 and VP1 were introduced to further investigate their roles played in cell tropism. These mutations cooperated in the growth of CV-A10 in Vero cells. Particularly, the valine to isoleucine mutation at the position VP1-236 (V1236I) was found to significantly restrict viral uncoating in Vero cells. Co-immunoprecipitation assays showed that the release of viral RNA from the KREMEN1 receptor-binding virions was restricted in r0195-V1236I compared with the parental strain r0195 (a RD+/Vero+ strain). Overall, this study highlights the dominant effect of structural proteins in CV-A10 adaption in Vero cells and the importance of V1236 in viral uncoating, providing a foundation for the mechanism study of CV-A10 cell tropism, and facilitating the development of vaccine candidates.

show abstract

Involvement of VCP/UFD1/Nucleolin in the viral entry of Enterovirus A species

Cited by 9 publications

References 40 publications

Valosin-Containing Protein/p97 Plays Critical Roles in the Japanese Encephalitis Virus Life Cycle

Valosin-Containing Protein/p97 Plays Critical Roles in the Japanese Encephalitis Virus Life Cycle

Seneca Valley Virus 3C ^pro Mediates Cleavage and Redistribution of Nucleolin To Facilitate Viral Replication

Identification of Critical Amino Acids of Coxsackievirus A10 Associated with Cell Tropism and Viral RNA Release during Uncoating

Contact Info

Product

Resources

About

Involvement of VCP/UFD1/Nucleolin in the viral entry of Enterovirus A species

Cited by 9 publications

References 40 publications

Valosin-Containing Protein/p97 Plays Critical Roles in the Japanese Encephalitis Virus Life Cycle

Valosin-Containing Protein/p97 Plays Critical Roles in the Japanese Encephalitis Virus Life Cycle

Seneca Valley Virus 3C pro Mediates Cleavage and Redistribution of Nucleolin To Facilitate Viral Replication

Identification of Critical Amino Acids of Coxsackievirus A10 Associated with Cell Tropism and Viral RNA Release during Uncoating

Contact Info

Product

Resources

About

Seneca Valley Virus 3C ^pro Mediates Cleavage and Redistribution of Nucleolin To Facilitate Viral Replication