Up-Regulation of Hepatitis C Virus Replication and Production by Inhibition of MEK/ERK Signaling

Ndjomou, Jean; Park, InWoo; Liu, Ying; Mayo, Lindsey D.; He, Johnny J.

doi:10.1371/journal.pone.0007498

Cited by 20 publications

(15 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other groups also reported that inhibition of MEK/ERK signaling enhanced HCV propagation (26). We showed that silencing of Abi1 resulted in enhancement of ERK activation.…”

Section: Ns5a Interacts With Abi1 and Regulates Mek/erk Signalingsupporting

confidence: 57%

Hepatitis C Virus Nonstructural 5A Protein Interacts with Abelson Interactor 1 and Modulates Epidermal Growth Factor-mediated MEK/ERK Signaling Pathway

Huynh

Lim

Tran

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The propagation of hepatitis C virus (HCV) is highly dependent on host cellular factors. To identify the cellular factors involved in HCV propagation, we have previously performed protein microarray assays using the HCV nonstructural 5A (NS5A) protein as a probe. Of ϳ9,000 host proteins immobilized in a microarray, ϳ90 cellular proteins were identified as HCV NS5A interacting partners. Of these candidates, we selected Abelson interactor 1 (Abi1) for further characterization. Binding of HCV NS5A to Abi1 was verified by both in vitro pulldown and coimmunoprecipitation assays. HCV NS5A interacted with Abi1 through regions I ؉ II of Abi1 and domain I of NS5A. We further demonstrated that Abi1 colocalized with the HCV NS5A protein in the cytoplasm. We showed that NS5A inhibited epidermal growth factor-mediated ERK and Egr1 activations and this inhibitory activity of NS5A was nullified in Abi1-knockdown cells. Moreover, silencing of Abi1 expression impaired HCV replication, whereas overexpression of Abi1 promoted HCV propagation. Collectively, these data indicate that HCV exploits host Abi1 protein via NS5A to modulate MEK/ERK signaling pathway for its own propagation. Hepatitis C virus (HCV)3 is a major etiologic agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. HCV is an enveloped virus with a positive-sense, singlestranded RNA genome. HCV belongs to the genus Hepacivirus within the Flaviviridae family (1). The HCV genome is ϳ9.6 kb in length and encodes a 3,010-amino acid protein from a single large open reading frame. This polyprotein precursor undergoes cleavage by both host cellular and viral proteases to generate 3 structural proteins (core, E1, and E2) and 7 nonstructural proteins (p7 and NS2 to NS5B) (2). The structural proteins are the components of the virion, whereas the nonstructural proteins are involved in the replication of the viral genome. Nonstructural 5A (NS5A) is a multifunctional protein and interacts with many cellular proteins to regulate cellular signaling pathways and viral propagation. NS5A contains three consensus proline-rich PXXP motifs, which bind to SH3 domains. These motifs are commonly found in many cellular signaling molecules (3). NS5A modulates the MAPK signaling pathway to regulate cell growth and activation. NS5A specifically interacts with the two SH3 domains of growth factor receptorbound protein 2 (Grb2) and inhibits the MAPK/ERK pathway (4). NS5A containing mutations within the C-terminal prolinerich motif neither interacts with Grb2 nor inhibits epidermal growth factor (EGF)-stimulated ERK1/2 phosphorylation (5-7). Furthermore, NS5A expressed in recombinant herpes simplex virus-infected cells also interacts with Grb2 and inhibits the Erk1/2 signaling pathway (8). These data indicate that NS5A regulates the MAPK pathway via Grb2. However, the exact molecular mechanisms by which NS5A interferes with function of Grb2 remains unclear.Abelson interactor 1 (Abi1), also known as E3B1, is an adaptor protein in the receptor tyrosine kinase (RTK) sig...

show abstract

“…Other groups also reported that inhibition of MEK/ERK signaling enhanced HCV propagation (26). We showed that silencing of Abi1 resulted in enhancement of ERK activation.…”

Section: Ns5a Interacts With Abi1 and Regulates Mek/erk Signalingsupporting

confidence: 57%

Hepatitis C Virus Nonstructural 5A Protein Interacts with Abelson Interactor 1 and Modulates Epidermal Growth Factor-mediated MEK/ERK Signaling Pathway

Huynh

Lim

Tran

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…During virus infection, MAPKs can either be utilized to promote virus-specific protein synthesis and subsequent progeny virus production [14,15,42], or act as negative regulators of virus replication [43]. The different MAPK cascades during influenza virus infection serve as novel potential targets for antiviral intervention [44].…”

Section: Discussionmentioning

confidence: 99%

Involvement of the mitogen-activated protein kinase pathway in soft-shelled turtle iridovirus-induced apoptosis

Huang

Cai

et al. 2011

Apoptosis

View full text Add to dashboard Cite

Iridoviruses are large DNA viruses that infect invertebrates and poikilothermic vertebrates, and result in significant economic losses in aquaculture production, and drastic declines in amphibian populations. Soft-shelled turtle iridovirus (STIV) is the causative agent of severe systemic diseases in farm-raised soft-shelled turtles (Trionyx sinensis). In the present study, the mechanisms of STIV-induced cell death and the roles of the mitogen-activated protein kinase (MAPK) signaling pathway were investigated. STIV infection evoked typical apoptosis in fish cells, as demonstrated by the formation of apoptotic bodies, positive terminal deoxynucleotidyl transferase-mediated nicked-end labeling, and caspase-3 activation. The translocation of cytochrome c from mitochondria to cytoplasm, and caspase-9 activation suggested that a mitochondria-mediated pathway was involved in STIV-induced apoptosis. Moreover, MAPK pathways, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK signaling were activated during STIV infection. Using specific inhibitors, we found that MAPK signaling molecules, including ERK, JNK and p38 MAPK, were important for virus release, whereas, only ERK and p38 MAPK were involved in STIV-induced apoptosis by modulating caspase-3 activity. Taken together, our findings shed light on the roles of the MAPK signaling pathway in iridovirus-induced apoptosis and virus replication, which provides new insights into understanding iridovirus-host interaction.

show abstract

“…Both spectral counting and dimethyl-labeling quantification revealed altered activity in MAPK pathways kinases. As shown in Table 1, the activities of mitogen-activated protein kinase 1 (MAPK1) and dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1), the kinase that activates MAPK1, 63 were downregulated in HCV-containing cells compared to naıve cells (Table 1). Pathway enrichment analysis of differentially active kinases indicates that the MAPK pathway is strongly inhibited by HCV (Table 3).…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

Profiling Kinase Activity during Hepatitis C Virus Replication Using a Wortmannin Probe

et al. 2015

View full text Add to dashboard Cite

To complete its life cycle, the hepatitis C virus (HCV) induces changes to numerous aspects of its host cell. As kinases act as regulators of many pathways utilized by HCV, they are likely enzyme targets for virally induced inhibition or activation. Herein, we used activity-based protein profiling (ABPP), which allows for the identification of active enzymes in complex protein samples and the quantification of their activity, to identify kinases that displayed differential activity in HCV-expressing cells. We utilized an ABPP probe, wortmannin-yne, based on the kinase inhibitor wortmannin, which contains a pendant alkyne group for bioconjugation using bioorthogonal chemistry. We observed changes in the activity of kinases involved in the mitogen-activated protein kinase pathway, apoptosis pathways, and cell cycle control. These results establish changes to the active kinome, as reported by wortmannin-yne, in the proteome of human hepatoma cells actively replicating HCV. The observed changes include kinase activity that affect viral entry, replication, assembly, and secretion, implying that HCV is regulating the pathways that it uses for its life cycle through modulation of the active kinome.

show abstract

Up-Regulation of Hepatitis C Virus Replication and Production by Inhibition of MEK/ERK Signaling

Cited by 20 publications

References 30 publications

Hepatitis C Virus Nonstructural 5A Protein Interacts with Abelson Interactor 1 and Modulates Epidermal Growth Factor-mediated MEK/ERK Signaling Pathway

Hepatitis C Virus Nonstructural 5A Protein Interacts with Abelson Interactor 1 and Modulates Epidermal Growth Factor-mediated MEK/ERK Signaling Pathway

Involvement of the mitogen-activated protein kinase pathway in soft-shelled turtle iridovirus-induced apoptosis

Profiling Kinase Activity during Hepatitis C Virus Replication Using a Wortmannin Probe

Contact Info

Product

Resources

About