Role of MAPK/MNK1 signaling in virus replication

Kumar, Ram; Khandelwal, Nitin; Riyesh, Thachamvally; Tripathi, Bhupendra Nath; Barua, Sanjay; Kashyap, S. K.; Maherchandani, Sunil; Kumar, Naveen

doi:10.1016/j.virusres.2018.05.028

Cited by 113 publications

(140 citation statements)

References 269 publications

(321 reference statements)

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“…RPSA induces the dephosphorylation of kinases ERK, JNK, and p38 and decreases the activity of the three MAPK cascades in tumor cell lines (13). The MAPK pathway is activated and manipulated by diverse group of viruses during viral infection (35). However, little is known about the MAPK signal pathway in FMDV-infected cells.…”

Section: Discussionmentioning

confidence: 99%

“…Excessive inflammation is becoming accepted as a critical factor in many viral infection diseases. MAPKs are important regulators of inflammatory cytokine and chemokine expression, and many viruses have been shown to exploit MAPK signaling by causing excessive inflammation for their own replication (20,28,35). Excessive inflammatory response has been associated with FMDV-induced diseases (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

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Foot-and-Mouth Disease Virus Capsid Protein VP1 Interacts with Host Ribosomal Protein SA To Maintain Activation of the MAPK Signal Pathway and Promote Virus Replication

Zhu

Zhang

et al. 2020

J Virol

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Foot-and-mouth disease virus (FMDV) is the causative agent of foot-and-mouth disease, a highly contagious, economically important viral disease. The structural protein VP1 plays significant roles during FMDV infection. Here, we identified that VP1 interacted with host ribosomal protein SA (RPSA). RPSA is a viral receptor for dengue virus and classical swine fever virus infections. However, the incubation of susceptible cells using the anti-RPSA antibodies did not block the infection of FMDV. Overexpression of porcine RPSA in the insusceptible cells could not trigger FMDV infection, suggesting that RPSA was not responsible for FMDV entry and infection. On the contrary, we found that overexpression of RPSA suppressed FMDV replication, and knockdown of RPSA enhanced FMDV replication. We further determined that FMDV infection activated the mitogen-activated protein kinase (MAPK) pathway and demonstrated that MAPK pathway activation was critically important for FMDV replication. RPSA negatively regulated MAPK pathway activation during FMDV infection and displayed an antiviral function. FMDV VP1 interacted with RPSA to abrogate the RPSA-mediated suppressive role in MAPK pathway activation. Together, our study indicated that MAPK pathway activation was required for FMDV replication and that host RPSA played a negatively regulatory role on MAPK pathway activation to suppress FMDV replication. FMDV VP1 bound to RPSA to promote viral replication by repressing RPSA-mediated function and maintaining the activation of MAPK signal pathway. IMPORTANCE Identification of virus-cell interactions is essential for making strategies to limit virus replication and refine the models of virus replication. This study demonstrated that FMDV utilized the MAPK pathway for viral replication. The host RPSA protein inhibited FMDV replication by suppressing the activation of the MAPK pathway during FMDV infection. FMDV VP1 bound to RPSA to repress the RPSA-mediated regulatory effect on MAPK pathway activation. This study revealed an important implication of the MAPK pathway for FMDV infection and identified a novel mechanism by which FMDV VP1 has evolved to interact with RPSA and maintain the activation of the MAPK pathway, elucidating new information regarding the signal reprogramming of host cells by FMDV.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Foot-and-Mouth Disease Virus Capsid Protein VP1 Interacts with Host Ribosomal Protein SA To Maintain Activation of the MAPK Signal Pathway and Promote Virus Replication

Zhu

Zhang

et al. 2020

J Virol

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“…Why does this array of unrelated viruses target IRE1? Beyond the aforementioned XBP1s transcription program, IRE1 can activate the JNK signalling pathway [107], which plays important roles in viral replication, cellular stress responses, and cell fate [108,109]. For HSV-1, IRE1 activation could activate JNK, which has been shown to support viral replication in multiple cell types [101].…”

Section: Discussionmentioning

confidence: 99%

KSHV activates unfolded protein response sensors but suppresses downstream transcriptional responses to support lytic replication

Johnston

McCormick

2018

Preprint

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Herpesviruses usurp host cell protein synthesis machinery to convert viral mRNAs into proteins, and the endoplasmic reticulum (ER) to ensure proper folding, post-translational modification and trafficking of secreted viral proteins. Overloading ER folding capacity activates the unfolded protein response (UPR), whereby displacement of the ER chaperone BiP activates UPR sensor proteins ATF6, PERK and IRE1 to initiate transcriptional responses to increase catabolic processes and ER folding capacity, while suppressing bulk protein synthesis. Kaposi’s sarcoma-associated herpesvirus (KSHV) can be reactivated from latency by chemical induction of ER stress, whereby the IRE1 endoribonuclease cleaves XBP1 mRNA, resulting in a ribosomal frameshift that yields the XBP1s transcription factor that transactivates the promoter of K-RTA, the viral lytic switch protein. By incorporating XBP1s responsive elements in the K-RTA promoter KSHV appears to have evolved a mechanism to respond to ER stress. Here, we report that following reactivation from latency, KSHV lytic replication causes activation of ATF6, PERK and IRE1 UPR sensor proteins. UPR sensor activation is required for efficient KSHV lytic replication; genetic or pharmacologic inhibition of each UPR sensor diminishes virion production. Despite strong UPR sensor activation during KSHV lytic replication, downstream UPR transcriptional responses were restricted; 1) ATF6 was cleaved to release the ATF6(N) transcription factor but known ATF6(N)-responsive genes were not transcribed; 2) PERK phosphorylated eIF2α but ATF4 did not accumulate as expected; 3) IRE1 caused XBP1 mRNA splicing, but XBP1s protein failed to accumulate and XBP1s-responsive genes were not transcribed. Remarkably, complementation of XBP1s deficiency during KSHV lytic replication by ectopic expression inhibited the production of infectious virions in a dose-dependent manner. Therefore, while XBP1s plays an important role in reactivation from latency, it inhibits later steps in lytic replication, which the virus overcomes by preventing its synthesis. Taken together, these findings suggest that KSHV hijacks UPR sensors to promote efficient viral replication while sustaining ER stress.Author summaryHuman herpesvirus-8 is the most recently discovered human herpesvirus, and it is the infectious cause of Kaposi’s sarcoma, which is why it’s also known as Kaposi’s sarcoma-associated herpesvirus (KSHV). Like all herpesviruses, KSHV replicates in the cell nucleus and uses host cell machinery to convert viral genes into proteins. Some of these proteins are synthesized, folded and modified in the endoplasmic reticulum (ER) and traverse the cellular secretory apparatus. Because the virus heavily utilizes the ER to make and process proteins, there is potential to overwhelm the system, which could impede viral replication and in extreme cases, kill the cell. Normally, when demands on the protein folding machinery are exceeded then misfolded proteins accumulate and activate the unfolded protein response (UPR). The UPR resolves ER stress by putting the brakes on synthesis of many proteins, while signaling to the nucleus to turn on a program that aims to correct this imbalance. Previous work has shown that KSHV is ‘wired’ to sense ER stress, which it uses to reactivate from a largely inactive state known as latency, in order to make more viruses. Specifically, a UPR sensor protein called IRE1 senses the accumulation of unfolded proteins in the ER and rededicates a gene called XBP1 to the production of a transcription factor called XBP1s through an unconventional cytoplasmic mRNA splicing event. XBP1s travels to the cell nucleus and stimulates the production of a collection of proteins that mitigate ER stress. In latently infected cells, XBP1s also binds to the KSHV genome and causes the production of K-RTA, a viral transcription factor that initiates the switch from latency to productive lytic replication. This achieves stress-induced initiation of KSHV replication, but nothing is known about how ER stress and the UPR affect progress through the KSHV replication cycle. Here we show that as KSHV replication progresses, all three known UPR sensor proteins, IRE1, ATF6 and PERK, are activated, which is required for efficient viral replication. Normally, activation of each of these three sensor proteins communicates a unique signal to the cell nucleus to stimulate the production of ER stress mitigating proteins, but in KSHV lytic replication all downstream communication is stymied. The failure to resolve ER stress would normally be expected to put the virus at a disadvantage, but we demonstrate that reversal of this scenario is worse; when we add extra XBP1s to the system to artificially stimulate the production of UPR responsive genes, virus replication is blocked at a late stage and no progeny viruses are released from infected cells. Taken together, these observations suggest that KSHV requires UPR sensor protein activation to replicate but has dramatically altered the outcome to prevent the synthesis of new UPR proteins and sustain stress in the ER compartment.

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“…MAPK signaling cascade is activated in response to external stress signals of the 3 MAP kinases (ERK, JNK, and p38 isoforms) with the subsequent stimulation of pro-inflammatory cytokines by JNK and p38 signaling [50][51][52] . In the nucleus, activated JNK and p38 promote multiple effector proteins, including NF-κB, c-Jun, STAT1 53 . These effector proteins have been implicated in viral infections such as influenza A and HSV-1 and their dysregulation by pathogens is associated with impaired antiviral response by the host 53,54 .…”

Section: Common Signal Transduction Pathwaysmentioning

confidence: 99%

“…In the nucleus, activated JNK and p38 promote multiple effector proteins, including NF-κB, c-Jun, STAT1 53 . These effector proteins have been implicated in viral infections such as influenza A and HSV-1 and their dysregulation by pathogens is associated with impaired antiviral response by the host 53,54 . The downregulation of the MAPK pathway in the BCGvaccinated group (Figure 10) may be able to partially reverse the upregulation induced by the SARS-CoV-2 virus.…”

Section: Common Signal Transduction Pathwaysmentioning

confidence: 99%

Hidden in plain sight: The effects of BCG vaccination in COVID-19 pandemic

Toraih

Sedhom²,

Dokunmu

et al. 2020

Preprint

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To investigate the relationship between BCG vaccination and SARS-CoV-2 by bioinformatic approach. Two datasets for Sars-CoV-2 infection group and BCG-vaccinated group were downloaded. Differentially Expressed Genes were identified.Gene ontology and pathways were functionally enriched, and networking was constructed in NetworkAnalyst. Lastly, correlation between post-BCG vaccination and COVID-19 transcriptome signatures were established. A total of 161 DEGs (113 upregulated DEGs and 48 downregulated genes) were identified in the Sars-CoV-2 group. In the pathway enrichment analysis, cross-reference of upregulated KEGG pathways in Sars-CoV-2 with downregulated counterparts in the BCGvaccinated group, resulted in the intersection of 45 common pathways, accounting for 86.5% of SARS-CoV-2 upregulated pathways. Of these intersecting pathways, a vast majority were immune and inflammatory pathways with top significance in IL-17, TNF, NOD-like receptors, and NF-κB signaling pathways. Our data suggests BCG-vaccination may incur a protective role in COVID-19 patients until a targeted vaccine is developed. Supplementary Materials (https://drive.google.com/open?id=15Na738L282XNaQAJUh0cZf1WoG9jJfzJ)2|P a g e 4|P a g e Data pre-processing and differential expression analysis After background correction of raw expression data, mapped multiple probes to the same genes were summarized to gene levels by using the median. Genes were filtered out if variance percentile rank lower than the threshold (set at 15%) or low relative abundance (average expression signal) below 5%. To ensure similar expression distributions of each sample across the entire experiment, normalization by log2 transformation method was performed. The quality of the normalized dataset was checked with the box plot and density plot, and the Benjamini and Hochberg method was selected for the multiple testing correction. Using the Limma R package available on Bioconductor (http://bioconductor.org/packages/release/bioc/html/limma.html), differentially expressed genes (DEGs) were identified in the microarray dataset. Genes with false discovery rate (FDR) <0.05 and log2-fold change (FC) ≥1.0 were considered as significantly differentially expressed and subjected to further analysis. For the RNA seq data of BCG vaccine, gene expression signature was generated by comparing gene expression levels of the post-vaccination groups with the control group at day 0. Altered patterns of gene expression were defined through each experimental time (FC>1|P<0.05). To visually identify the similarities and differences between different cell line samples, principal component analysis (PCA) was plotted to project high-dimensional data into lower dimensions using linear transformation. Functional Enrichment AnalysisGene Ontology (GO) database for function annotation of genes was used to analyze the DEGs at the functional level in terms of biological processes, molecular function, and cellular component domains 34 . Pathway functional analysis was performed in the Kyoto Encyclopedia of Gen...

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Role of MAPK/MNK1 signaling in virus replication

Cited by 113 publications

References 269 publications

Foot-and-Mouth Disease Virus Capsid Protein VP1 Interacts with Host Ribosomal Protein SA To Maintain Activation of the MAPK Signal Pathway and Promote Virus Replication

Foot-and-Mouth Disease Virus Capsid Protein VP1 Interacts with Host Ribosomal Protein SA To Maintain Activation of the MAPK Signal Pathway and Promote Virus Replication

KSHV activates unfolded protein response sensors but suppresses downstream transcriptional responses to support lytic replication

Hidden in plain sight: The effects of BCG vaccination in COVID-19 pandemic

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