scholarly journals HDAC6 Restricts Influenza A Virus by Deacetylation of the RNA Polymerase PA Subunit

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Huan Chen ◽  
Yingjuan Qian ◽  
Xin Chen ◽  
Zhiyang Ruan ◽  
Yuetian Ye ◽  
...  
Keyword(s):  
Life Cycle ◽  
Rna Polymerase ◽  
Influenza A Virus ◽  
Influenza A ◽  
Molecular Mechanisms ◽  
Polymerase Activity ◽  
Negative Regulator ◽  
Host Protein ◽  
Spectrometric Analysis ◽  
Rna Polymerase Activity

ABSTRACT The life cycle of influenza A virus (IAV) is modulated by various cellular host factors. Although previous studies indicated that IAV infection is controlled by HDAC6, the deacetylase involved in the regulation of PA remained unknown. Here, we demonstrate that HDAC6 acts as a negative regulator of IAV infection by destabilizing PA. HDAC6 binds to and deacetylates PA, thereby promoting the proteasomal degradation of PA. Based on mass spectrometric analysis, Lys(664) of PA can be deacetylated by HDAC6, and the residue is crucial for PA protein stability. The deacetylase activity of HDAC6 is required for anti-IAV activity, because IAV infection was enhanced due to elevated IAV RNA polymerase activity upon HDAC6 depletion and an HDAC6 deacetylase dead mutant (HDAC6-DM; H216A, H611A). Finally, we also demonstrate that overexpression of HDAC6 suppresses IAV RNA polymerase activity, but HDAC6-DM does not. Taken together, our findings provide initial evidence that HDAC6 plays a negative role in IAV RNA polymerase activity by deacetylating PA and thus restricts IAV RNA transcription and replication. IMPORTANCE Influenza A virus (IAV) continues to threaten global public health due to drug resistance and the emergence of frequently mutated strains. Thus, it is critical to find new strategies to control IAV infection. Here, we discover one host protein, HDAC6, that can inhibit viral RNA polymerase activity by deacetylating PA and thus suppresses virus RNA replication and transcription. Previously, it was reported that IAV can utilize the HDAC6-dependent aggresome formation mechanism to promote virus uncoating, but HDAC6-mediated deacetylation of α-tubulin inhibits viral protein trafficking at late stages of the virus life cycle. These findings together will contribute to a better understanding of the role of HDAC6 in regulating IAV infection. Understanding the molecular mechanisms of HDAC6 at various periods of viral infection may illuminate novel strategies for developing antiviral drugs.

scholarly journals Mutational Analyses of the Influenza A Virus Polymerase Subunit PA Reveal Distinct Functions Related and Unrelated to RNA Polymerase Activity

PLoS ONE ◽  
2012 ◽  
Vol 7 (1) ◽  
pp. e29485 ◽  
Author(s):  
Yuhong Liang ◽  
Shamika Danzy ◽  
Luan Danh Dao ◽  
Tristram G. Parslow ◽  
Yuying Liang
Keyword(s):  
Rna Polymerase ◽  
Influenza A Virus ◽  
Influenza A ◽  
Polymerase Activity ◽  
Rna Polymerase Activity

scholarly journals A Novel Functional Site in the PB2 Subunit of Influenza A Virus Essential for Acetyl-CoA Interaction, RNA Polymerase Activity, and Viral Replication

2014 ◽  
Vol 289 (36) ◽  
pp. 24980-24994 ◽  
Author(s):  
Dai Hatakeyama ◽  
Masaki Shoji ◽  
Seiya Yamayoshi ◽  
Takenori Hirota ◽  
Monami Nagae ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Polymerase Activity ◽  
Functional Site ◽  
Acetyl Coa ◽  
Rna Polymerase Activity

scholarly journals DnaJA1/Hsp40 Is Co-Opted by Influenza A Virus To Enhance Its Viral RNA Polymerase Activity

2014 ◽  
Vol 88 (24) ◽  
pp. 14078-14089 ◽  
Author(s):  
M. Cao ◽  
C. Wei ◽  
L. Zhao ◽  
J. Wang ◽  
Q. Jia ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Influenza A Virus ◽  
Influenza A ◽  
Polymerase Activity ◽  
Viral Rna ◽  
Rna Polymerase Activity

scholarly journals Measles Virus Nonstructural C Protein Modulates Viral RNA Polymerase Activity by Interacting with Host Protein SHCBP1

2013 ◽  
Vol 87 (17) ◽  
pp. 9633-9642 ◽  
Author(s):  
M. Ito ◽  
M. Iwasaki ◽  
M. Takeda ◽  
T. Nakamura ◽  
Y. Yanagi ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Measles Virus ◽  
Polymerase Activity ◽  
Viral Rna ◽  
Host Protein ◽  
C Protein ◽  
Rna Polymerase Activity

Influenza-C-virion-associated RNA-dependent RNA-polymerase activity

1984 ◽  
Vol 4 (8) ◽  
pp. 703-706 ◽  
Author(s):  
Arno Nagele ◽  
Herbert Meier-Ewert
Keyword(s):  
Rna Polymerase ◽  
Influenza A ◽  
Reaction Rate ◽  
Polymerase Activity ◽  
The Other ◽  
Radioactive Product ◽  
Rna Dependent Rna Polymerase ◽  
Influenza C Virus ◽  
Rna Polymerase Activity

The addition of detergent-solubilized influenza C virus to a reaction mixture containing ATP, CTP, GTP, [3H]UTP, and Mg2+ leads to the synthesis of an acid-insoluble, radioactive product) which is ribonucJease-sensitive. The dinucleoside monophosphate ApG clearly enhances the reaction rate, a fact which indicates that influenza C viruses follow the same strategy of transcription as influenza A and B viruses, the other members of the orthomyxovirus family.

scholarly journals A new promoter-binding site in the PB1 subunit of the influenza A virus polymerase

2006 ◽  
Vol 87 (3) ◽  
pp. 679-688 ◽  
Author(s):  
Tanis E. Jung ◽  
George G. Brownlee
Keyword(s):  
Rna Polymerase ◽  
Binding Site ◽  
Influenza A Virus ◽  
Binding Sites ◽  
Influenza A ◽  
Polymerase Activity ◽  
Viral Promoter ◽  
Putative Promoter ◽  
Virus Rna ◽  
Arginine Residues

The influenza A virus RNA-dependent RNA polymerase consists of three subunits PB1, PB2 and PA. The 5′ and 3′ terminal sequences of the viral RNA (vRNA) form the viral promoter and are bound by the PB1 subunit. The putative promoter-binding sites of the PB1 subunit have been mapped in previous studies but with contradictory results. The aim of the current study was to investigate the function of two evolutionary conserved regions in PB1 – from aa 233 to 249 and 269 to 281, which lie immediately N- and C-terminal, respectively, of a previously proposed binding site for the 3′ end of the vRNA promoter. The previously proposed binding site extended from aa 249 to 256 and centred on two phenylalanine residues (F251 and F254). However, the fact that F251 is required for polymerase activity was not confirmed here. Instead, it was proposed that the 233–249 region contains a new 5′ vRNA promoter-binding site, and arginine residues crucial for this activity were characterized. However, residues 269–281 were unlikely to be directly involved in promoter binding. These results are discussed in relation to the previous studies and a new model for vRNA promoter binding to the influenza RNA polymerase is presented.

scholarly journals Interaction of Nuclear Export Protein with G Protein Pathway Suppressor 2 (GPS2) Facilitates Influenza A Virus Replication by Weakening the Inhibition of GPS2 to RNA Synthesis and Ribonucleoprotein Assembly

2021 ◽  
Vol 95 (10) ◽  
Author(s):  
Wenxiao Gong ◽  
Xinglin He ◽  
Kun Huang ◽  
Yufei Zhang ◽  
Chengfei Li ◽  
...  
Keyword(s):  
Life Cycle ◽  
G Protein ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Nuclear Export ◽  
Influenza A ◽  
Rna Synthesis ◽  
Polymerase Activity ◽  
Nuclear Export Protein ◽  
Export Protein

ABSTRACT The nuclear export protein (NEP) serves multiple functions in the life cycle of influenza A virus (IAV). Identifying novel host proteins that interact with NEP and understanding their functions in IAV replication are of great interest. In this study, we screened and confirmed the direct interaction of G protein pathway suppressor 2 (GPS2) with NEP through a yeast two-hybrid screening assay and glutathione S-transferase pulldown and coimmunoprecipitation assays. Knockdown or knockout of GPS2 enhanced IAV titers, whereas overexpression of GPS2 impaired IAV replication, demonstrating that GPS2 acted as a negative host factor in IAV replication. Meanwhile, GPS2 inhibited viral RNA synthesis by reducing the assembly of IAV polymerase. Interestingly, IAV NEP interacted with GPS2 and mediated its nuclear export, thereby activating the degradation of GPS2. Thus, NEP-GPS2 interaction weakened the inhibition of GPS2 to viral polymerase activity and benefited virus replication. Overall, this study identified the novel NEP-binding host partner GPS2 as a critical host factor to participate in IAV replication. These findings provided novel insights into the interactions between IAV and host cells, revealing a new function for GPS2 during IAV replication. IMPORTANCE NEP is proposed to play multiple biologically important roles in the life cycle of IAV, which largely relies on host factors by interaction. Our study demonstrated that GPS2 could reduce the interaction between polymerase basic 1 (PB1) and PB2 and interfere with viral ribonucleoprotein (vRNP) assembly. Thus, GPS2 inhibited the RNA synthesis of IAV and negatively regulated its replication. Importantly, IAV NEP interacted with GPS2 and mediated the nuclear export of GPS2, thereby activating the degradation of GPS2. Thus, NEP-GPS2 interaction weakened the inhibition of GPS2 to viral polymerase activity and benefited virus replication.

scholarly journals Suramin, Penciclovir and Anidulafungin bind nsp12, which governs the RNA-dependent-RNA polymerase activity of SARS-CoV-2, with higher interaction energy than Remdesivir, indicating potential in the treatment of Covid-19

2020 ◽  
Author(s):  
Sanjay Kumar Dey ◽  
Manisha Saini ◽  
Chetna Dhembla ◽  
Shruti Bhatt ◽  
A. Sai Rajesh ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Drug Repositioning ◽  
Polymerase Activity ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Dimensional Structure ◽  
Rna Dependent Rna Polymerase ◽  
Rna Polymerase Activity

Structured abstract:Introduction: COVID-19, for which no vaccine or confirmed therapeutic agents are available, has claimed over 7,30,000 lives globally. A feasible and quicker method to resolve this problem may be ‘drug repositioning’.Areas covered: We investigated selected FDA and WHO-EML approved drugs based on their previously promising potential as antivirals, antibacterials or antifungals. These drugs were docked onto the three-dimensional structure of nsp12 protein, which reigns the RNA-dependent RNA polymerase activity of SARS-CoV-2 and is one of the major therapeutic targets for corona viruses. Inhibitor-protein complexes were also subjected to molecular dynamics simulation. The binding energies and the mode of interaction of the active site of the protein with the drugs were evaluated.Results: Suramin, Penciclovir and Anidulafungin were found to bind to nsp12 with similar binding energies as that of Remdesivir, which is currently being used in the treatment of COVID-19. In addition, recent experimental evidences indicate that these drugs exhibit antiviral efficacy against SARS-CoV-2. Thus, they might have a prospective therapeutic potential against the key viral enzyme.Expert opinion: Repurposed drugs will provide viable options for the treatment of COVID-19 and insight into the molecular mechanisms by which these potential drug candidates exhibit anti-SARSCoV-2 activity.

scholarly journals Phosphorylation of JIP4 at S730 presents anti-viral properties against influenza A virus infection

2021 ◽  
Author(s):  
Juliana Del Sarto ◽  
Vanessa Gerlt ◽  
Marcel Edgar Friedrich ◽  
Darisuren Anhlan ◽  
Viktor Wixler ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Direct Reduction ◽  
Polymerase Activity ◽  
Host Protein ◽  
Protein Accumulation ◽  
Viral Polymerase ◽  
Mrna Accumulation ◽  
Interacting Protein ◽  
Altered Expression

AbstractInfluenza A virus (IAV) is the causative agent of flu disease that results in annual epidemics and occasional pandemics. IAV alters several signaling pathways of the cellular host response in order to promote its replication. Therefore, our group investigates different host cell pathways modified in IAV infection as promising targets for long-lasting therapeutic approaches. Here, we show that c-Jun NH2-terminal kinase (JNK)-interacting protein (JIP) 4 is dynamically phosphorylated in IAV infection. Lack of JIP4 resulted in higher virus titers with significant differences in viral protein and mRNA accumulation as early as within the first replication cycle. In accordance, decreased IAV titers and protein accumulation was observed during overexpression of JIP4. Strikingly, the anti-viral function of JIP4 does neither originate from a modulation of JNK or p38 MAPK pathways, nor from altered expression of interferons or interferon-stimulated genes, but rather from a direct reduction of viral polymerase activity. Furthermore, interference of JIP4 with IAV replication is linked to phosphorylation of the serine at position 730, that is sufficient to impede with the viral polymerase and is mediated by the Raf/MEK/ERK pathway. Collectively, we provide evidence that JIP4, a host protein modulated in IAV infection, exhibits anti-viral properties that are dynamically controlled by its phosphorylation at S730.

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