scholarly journals A new role of neuraminidase (NA) in the influenza virus life cycle: implication for developing NA inhibitors with novel mechanism of action

2016 ◽  
Vol 26 (4) ◽  
pp. 242-250 ◽  
Author(s):  
Jie Yang ◽  
Shuwen Liu ◽  
Lanying Du ◽  
Shibo Jiang
Keyword(s):  
Influenza Virus ◽  
Life Cycle ◽  
Mechanism Of Action ◽  
Virus Life Cycle

scholarly journals Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle

2021 ◽  
Vol 22 (9) ◽  
pp. 4438
Author(s):  
Jessica Proulx ◽  
Kathleen Borgmann ◽  
In-Woo Park
Keyword(s):  
Immune Response ◽  
Life Cycle ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Antiviral Immune Response ◽  
Cellular Processes ◽  
Virus Life Cycle ◽  
Infected Cells ◽  
Dependent Processes

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication.

scholarly journals Intracellular Expression of Camelid Single-Domain Antibodies Specific for Influenza Virus Nucleoprotein Uncovers Distinct Features of Its Nuclear Localization

2014 ◽  
Vol 89 (5) ◽  
pp. 2792-2800 ◽  
Author(s):  
Joseph Ashour ◽  
Florian I. Schmidt ◽  
Leo Hanke ◽  
Juanjo Cragnolini ◽  
Marco Cavallari ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Life Cycle ◽  
Nuclear Localization ◽  
Nuclear Import ◽  
Rna Viruses ◽  
Single Domain ◽  
Single Domain Antibody ◽  
Virus Life Cycle ◽  
Domain Antibody ◽  
Chemical Inhibition

ABSTRACTPerturbation of protein-protein interactions relies mostly on genetic approaches or on chemical inhibition. Small RNA viruses, such as influenza A virus, do not easily lend themselves to the former approach, while chemical inhibition requires that the target protein be druggable. A lack of tools thus constrains the functional analysis of influenza virus-encoded proteins. We generated a panel of camelid-derived single-domain antibody fragments (VHHs) against influenza virus nucleoprotein (NP), a viral protein essential for nuclear trafficking and packaging of the influenza virus genome. We show that these VHHs can target NP in living cells and perturb NP's function during infection. Cytosolic expression of NP-specific VHHs (αNP-VHHs) disrupts virus replication at an early stage of the life cycle. Based on their specificity, these VHHs fall into two distinct groups. Both prevent nuclear import of the viral ribonucleoprotein (vRNP) complex without disrupting nuclear import of NP alone. Different stages of the virus life cycle thus rely on distinct nuclear localization motifs of NP. Their molecular characterization may afford new means of intervention in the virus life cycle.IMPORTANCEMany proteins encoded by RNA viruses are refractory to manipulation due to their essential role in replication. Thus, studying their function and determining how to disrupt said function through pharmaceutical intervention are difficult. We present a novel method based on single-domain-antibody technology that permits specific targeting and disruption of an essential influenza virus protein in the absence of genetic manipulation of influenza virus itself. Characterization of such interactions may help identify new targets for pharmaceutical intervention. This approach can be extended to study proteins encoded by other viral pathogens.

scholarly journals Cellular Networks Involved in the Influenza Virus Life Cycle

2010 ◽  
Vol 7 (6) ◽  
pp. 427-439 ◽  
Author(s):  
Tokiko Watanabe ◽  
Shinji Watanabe ◽  
Yoshihiro Kawaoka
Keyword(s):  
Influenza Virus ◽  
Life Cycle ◽  
Cellular Networks ◽  
Virus Life Cycle

scholarly journals Ubiquitination Upregulates Influenza Virus Polymerase Function

2016 ◽  
Vol 90 (23) ◽  
pp. 10906-10914 ◽  
Author(s):  
James Kirui ◽  
Arindam Mondal ◽  
Andrew Mehle
Keyword(s):  
Influenza Virus ◽  
Life Cycle ◽  
Viral Proteins ◽  
Polymerase Activity ◽  
Viral Gene ◽  
Viral Polymerase ◽  
Ubiquitin Proteasome Pathway ◽  
Virus Life Cycle ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACTThe influenza A virus polymerase plays an essential role in the virus life cycle, directing synthesis of viral mRNAs and genomes. It is a trimeric complex composed of subunits PA, PB1, and PB2 and associates with viral RNAs and nucleoprotein (NP) to form higher-order ribonucleoprotein (RNP) complexes. The polymerase is regulated temporally over the course of infection to ensure coordinated expression of viral genes as well as replication of the viral genome. Various host factors and processes have been implicated in regulation of the IAV polymerase function, including posttranslational modifications; however, the mechanisms are not fully understood. Here we demonstrate that ubiquitination plays an important role in stimulating polymerase activity. We show that all protein subunits in the RNP are ubiquitinated, but ubiquitination does not significantly alter protein levels. Instead, ubiquitination and an active proteasome enhance polymerase activity. Expression of ubiquitin upregulates polymerase function in a dose-dependent fashion, causing increased accumulation of viral RNA (vRNA), cRNA, and mRNA and enhanced viral gene expression during infection. Ubiquitin expression directly affects polymerase activity independent of nucleoprotein (NP) or ribonucleoprotein (RNP) assembly. Ubiquitination and the ubiquitin-proteasome pathway play key roles during multiple stages of influenza virus infection, and data presented here now demonstrate that these processes modulate viral polymerase activity independent of protein degradation.IMPORTANCEThe cellular ubiquitin-proteasome pathway impacts steps during the entire influenza virus life cycle. Ubiquitination suppresses replication by targeting viral proteins for degradation and stimulating innate antiviral signaling pathways. Ubiquitination also enhances replication by facilitating viral entry and virion disassembly. We identify here an addition proviral role of the ubiquitin-proteasome system, showing that all of the proteins in the viral replication machinery are subject to ubiquitination and this is crucial for optimal viral polymerase activity. Manipulation of the ubiquitin machinery for therapeutic benefit is therefore likely to disrupt the function of multiple viral proteins at stages throughout the course of infection.

scholarly journals DDX3 Interacts with Influenza A Virus NS1 and NP Proteins and Exerts Antiviral Function through Regulation of Stress Granule Formation

2016 ◽  
Vol 90 (7) ◽  
pp. 3661-3675 ◽  
Author(s):  
Sathya N. Thulasi Raman ◽  
Guanqun Liu ◽  
Hyun Mi Pyo ◽  
Ya Cheng Cui ◽  
Fang Xu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Life Cycle ◽  
Virus Infection ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Ns1 Protein ◽  
Antiviral Protein ◽  
Virus Life Cycle ◽  
Interaction Partners ◽  
Infected Cells

ABSTRACTDDX3 belongs to the DEAD box RNA helicase family and is a multifunctional protein affecting the life cycle of a variety of viruses. However, its role in influenza virus infection is unknown. In this study, we explored the potential role of DDX3 in influenza virus life cycle and discovered that DDX3 is an antiviral protein. Since many host proteins affect virus life cycle by interacting with certain components of the viral machinery, we first verified whether DDX3 has any viral interaction partners. Immunoprecipitation studies revealed NS1 and NP as direct interaction partners of DDX3. Stress granules (SGs) are known to be antiviral and do form in influenza virus-infected cells expressing defective NS1 protein. Additionally, a recent study showed that DDX3 is an important SG-nucleating factor. We thus explored whether DDX3 plays a role in influenza virus infection through regulation of SGs. Our results showed that SGs were formed in infected cells upon infection with a mutant influenza virus lacking functional NS1 (del NS1) protein, and DDX3 colocalized with NP in SGs. We further determined that the DDX3 helicase domain did not interact with NS1 and NP; however, it was essential for DDX3 localization in virus-induced SGs. Knockdown of DDX3 resulted in impaired SG formation and led to increased virus titers. Taken together, our results identified DDX3 as an antiviral protein with a role in virus-induced SG formation.IMPORTANCEDDX3 is a multifunctional RNA helicase and has been reported to be involved in regulating various virus life cycles. However, its function during influenza A virus infection remains unknown. In this study, we demonstrated that DDX3 is capable of interacting with influenza virus NS1 and NP proteins; DDX3 and NP colocalize in the del NS1 virus-induced SGs. Furthermore, knockdown of DDX3 impaired SG formation and led to a decreased virus titer. Thus, we provided evidence that DDX3 is an antiviral protein during influenza virus infection and its antiviral activity is through regulation of SG formation. Our findings provide knowledge about the function of DDX3 in the influenza virus life cycle and information for future work on manipulating the SG pathway and its components to fight influenza virus infection.

scholarly journals The role of Ran-binding protein 3 during influenza A virus replication

2013 ◽  
Vol 94 (5) ◽  
pp. 977-984 ◽  
Author(s):  
Rey Predicala ◽  
Yan Zhou
Keyword(s):  
Life Cycle ◽  
Influenza A Virus ◽  
Nuclear Export ◽  
Influenza A ◽  
Binding Protein ◽  
Late Phase ◽  
Nuclear Retention ◽  
Interacting Protein ◽  
Virus Life Cycle

Influenza A virus vRNP nuclear export is CRM1-dependent. Ran-binding protein 3 (RanBP3) is a Ran-interacting protein that is best known for its role as a cofactor of CRM1-mediated cargo nuclear export. In this study, we investigated the role of RanBP3 during the influenza A virus life cycle. We found that RanBP3 was phosphorylated at Ser58 in the early and late phases of infection. Knockdown of RanBP3 expression led to vRNP nuclear retention, suggesting that RanBP3 is involved in vRNP nuclear export. Moreover, we demonstrated that the function of RanBP3 during vRNP nuclear export is regulated by phosphorylation at Ser58, and that RanBP3 phosphorylation is modulated by both PI3K/Akt and Ras/ERK/RSK pathways in the late phase of viral infection.

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