Novel Roles of Focal Adhesion Kinase in Cytoplasmic Entry and Replication of Influenza A Viruses

Elbahesh, Husni; Cline, Troy; Baranovich, Tatiana; Govorkova, Elena A.; Schultz‐Cherry, Stacey; Russell, Charles J.

doi:10.1128/jvi.00530-14

Cited by 47 publications

(44 citation statements)

References 60 publications

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“…Human metapneumovirus (hMPV) stocks were propagated and viral titers were determined in LLC-MK2 cells (28). Viral infections were conducted as described previously (29,30). Endpoint dilution-based 50% tissue culture infective dose (TCID 50 ) assays to determine progeny infectious-virus titers of IAV/IBV in cell-free culture supernatants were performed in 96-well plates on monolayers of MDCK cells (24,30,31).…”

Section: Methodsmentioning

confidence: 99%

The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis

Liu

Shen

et al. 2016

J Virol

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Accumulating data suggest that tripartite-motif-containing (TRIM) proteins participate in host responses to viral infections, either by acting as direct antiviral restriction factors or through regulating innate immune signaling of the host. Of >70 TRIMs, TRIM56 is a restriction factor of several positive-strand RNA viruses, including three members of the family Flaviviridae (yellow fever virus, dengue virus, and bovine viral diarrhea virus) and a human coronavirus (OC43), and this ability invariably depends upon the E3 ligase activity of TRIM56. However, the impact of TRIM56 on negative-strand RNA viruses remains unclear. Here, we show that TRIM56 puts a check on replication of influenza A and B viruses in cell culture but does not inhibit Sendai virus or human metapneumovirus, two paramyxoviruses. Interestingly, the anti-influenza virus activity was independent of the E3 ligase activity, B-box, or coiled-coil domain. Rather, deletion of a 63-residue-long C-terminal-tail portion of TRIM56 abrogated the antiviral function. Moreover, expression of this short C-terminal segment curtailed the replication of influenza viruses as effectively as that of full-length TRIM56. Mechanistically, TRIM56 was found to specifically impede intracellular influenza virus RNA synthesis. Together, these data reveal a novel antiviral activity of TRIM56 against influenza A and B viruses and provide insights into the mechanism by which TRIM56 restricts these medically important orthomyxoviruses. IMPORTANCE Options to treat influenza are limited, and drug-resistant influenza virus strains can emerge through minor genetic changes. Understanding novel virus-host interactions that alter influenza virus fitness may reveal new targets/approaches for therapeutic interventions.We show here that TRIM56, a tripartite-motif protein, is an intrinsic host restriction factor of influenza A and B viruses. Unlike its antiviral actions against positive-strand RNA viruses, the anti-influenza virus activity of TRIM56 was independent of the E3 ligase activity. Rather, expression of a short segment within the very C-terminal tail of TRIM56 inhibited the replication of influenza viruses as effectively as that of full-length TRIM56 by specifically targeting viral RNA synthesis. These data reveal the remarkable multifaceted activity of TRIM56, which has developed multiple domains to inhibit multiple viral families. They also raise the possibility of developing a broad-spectrum, TRIM56-based antiviral approach for addition to influenza prophylaxis and/or control strategies.

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Section: Methodsmentioning

confidence: 99%

The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis

Liu

Shen

et al. 2016

J Virol

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“…Host miRNAs might have a probable role in blocking the entry of the virus, as they are found to be targeting the pathways needed for viral entry-PDGF receptor-like signaling (Soroceanu et al, 2008), Arf-6 signaling (García-Expósito et al, 2011), PI3K-Akt signaling (Diehl and Schaal, 2013), EGFR signaling (Zheng et al, 2014), signaling events mediated by focal adhesion kinase (Elbahesh et al, 2014), CDC42 signaling (Swaine and Dittmar, 2015), EphrinB-EPHB pathway (Wang et al, 2019), Cadherin signaling (Mateo et al, 2015), RTK signaling (Haqshenas and Doerig, 2019), etc (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulator miRNA pattern differences among SARS-CoV, SARS-CoV-2 and SARS-CoV-2 world-wide isolates delineated the mystery behind the epic pathogenicity and distinct clinical characteristics of pandemic COVID-19

Khan

Sany

Islam

et al. 2020

Preprint

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Detailed molecular mechanism of SARS-CoV-2 pathogenesis is still elusive to address its deadlier nature and to design effective theraputics. Here, we present our study elucidating the interplay between the SARS-CoV and SARS-CoV-2 viruses’; and host’s miRNAs, an epigenetic regulator, as a mode of pathogenesis, and enlightened how the SARS-CoV and SARS-CoV-2 infections differ in terms of their miRNA mediated interactions with host and its implications in the disease complexity. We have utilized computational approaches to predict potential host and viral miRNAs, and their possible roles in different important functional pathways. We have identified several putative host antiviral miRNAs that can target the SARS viruses, and also SARS viruses’ encoded miRNAs targeting host genes. In silico predicted targets were also integrated with SARS infected human cells microarray and RNA-seq gene expression data. Comparison of the host miRNA binding profiles on 67 different SARS-CoV-2 genomes from 24 different countries with respective country’s normalized death count surprisingly uncovered some miRNA clusters which are associated with increased death rates. We have found that induced cellular miRNAs can be both a boon and a bane to the host immunity, as they have possible roles in neutralizing the viral threat, parallelly, they can also function as proviral factors. On the other hand, from over representation analysis, interestingly our study revealed that although both SARS-CoV and SARS-CoV-2 viral miRNAs could target broad immune signaling pathways; only some of the SARS-CoV-2 miRNAs are found to uniquely target some immune signaling pathways like-autophagy, IFN-I signaling etc, which might suggest their immune-escape mechanisms for prolonged latency inside some hosts without any symptoms of COVID-19. Further, SARS-CoV-2 can modulate several important cellular pathways which might lead to the increased anomalies in patients with comorbidities like-cardiovascular diseases, diabetes, breathing complications, etc. This might suggest that miRNAs can be a key epigenetic modulator behind the overcomplications amongst the COVID-19 patients. Our results support that miRNAs of host and SARS-CoV-2 can indeed play a role in the pathogenesis which can be further concluded with more experiments. These results will also be useful in designing RNA therapeutics to alleviate the complications from COVID-19.

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“…For influenza virus, FAK has been shown to regulate two independent processes, one mediating viral entry and the other involved in viral RNA replication (44).…”

Section: Discussionmentioning

confidence: 99%

Focal Adhesion Kinase Is Involved in Rabies Virus Infection through Its Interaction with Viral Phosphoprotein P

Fouquet

Nikolić

Larrous

et al. 2015

J Virol

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The rabies virus (RABV) phosphoprotein P is a multifunctional protein: it plays an essential role in viral transcription and replication, and in addition, RABV P has been identified as an interferon antagonist. Here, a yeast two-hybrid screen revealed that RABV P interacts with the focal adhesion kinase (FAK). The binding involved the 106-to-131 domain, corresponding to the dimerization domain of P and the C-terminal domain of FAK containing the proline-rich domains PRR2 and PRR3. The P-FAK interaction was confirmed in infected cells by coimmunoprecipitation and colocalization of FAK with P in Negri bodies. By alanine scanning, we identified a single mutation in the P protein that abolishes this interaction. The mutant virus containing a substitution of Ala for Arg in position 109 in P (P.R109A), which did not interact with FAK, is affected at a posttranscriptional step involving protein synthesis and viral RNA replication. Furthermore, FAK depletion inhibited viral protein expression in infected cells. This provides the first evidence of an interaction of RABV with FAK that positively regulates infection. IMPORTANCERabies virus exhibits a small genome that encodes a limited number of viral proteins. To maintain efficient virus replication, some of them are multifunctional, such as the phosphoprotein P. We and others have shown that P establishes complex networks of interactions with host cell components. These interactions have revealed much about the role of P and about host-pathogen interactions in infected cells. Here, we identified another cellular partner of P, the focal adhesion kinase (FAK). Our data shed light on the implication of FAK in RABV infection and provide evidence that P-FAK interaction has a proviral function.

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Novel Roles of Focal Adhesion Kinase in Cytoplasmic Entry and Replication of Influenza A Viruses

Cited by 47 publications

References 60 publications

The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis

The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis

Epigenetic regulator miRNA pattern differences among SARS-CoV, SARS-CoV-2 and SARS-CoV-2 world-wide isolates delineated the mystery behind the epic pathogenicity and distinct clinical characteristics of pandemic COVID-19

Focal Adhesion Kinase Is Involved in Rabies Virus Infection through Its Interaction with Viral Phosphoprotein P

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