Human DNA Virus Exploitation of the MAPK-ERK Cascade

DuShane, Jeanne K.; Maginnis, Melissa S.

doi:10.3390/ijms20143427

Cited by 54 publications

(48 citation statements)

References 219 publications

(327 reference statements)

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“…The MAPK pathway is activated by many kinds of stimuli including endotoxic lipopolysaccharides (LPS), hyperosmolarity [44], proinflammatory cytokines and factors such as IL-1β, and PAF [45,46] and viral infections [47]. In the present study, activation of the MAPK signaling pathway was induced by LPS stimulation.…”

Section: Discussionmentioning

confidence: 65%

MicroRNA gga-miR-200a-3p modulates immune response via MAPK signaling pathway in chicken afflicted with necrotic enteritis

Pham

Ban

Lee

et al. 2020

Vet Res

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MicroRNAs (miRNAs) are small non-coding RNAs that contribute to host immune response as post-transcriptional regulation. The current study investigated the biological role of the chicken (Gallus gallus) microRNA-200a-3p (gga-miR-200a-3p), using 2 necrotic enteritis (NE) afflicted genetically disparate chicken lines, 6.3 and 7.2, as well as the mechanisms underlying the fundamental signaling pathways in chicken. The expression of gga-miR-200a-3p in the intestinal mucosal layer of NE-induced chickens, was found to be upregulated during NE infection in the diseasesusceptible chicken line 7.2. To validate the target genes, we performed an overexpression analysis of gga-miR-200a-3p using chemically synthesized oligonucleotides identical to gga-miR-200a-3p, reporter gene analysis including luciferase reporter assay, and a dual fluorescence reporter assay in cultured HD11 chicken macrophage cell lines. Gga-miR-200a-3p was observed to be a direct transcriptional repressor of ZAK, MAP2K4, and TGFβ2 that are involved in mitogen-activated protein kinase (MAPK) pathway by targeting the 3′-UTR of their transcripts. Besides, gga-miR-200a-3p may indirectly affect the expression of protein kinases including p38 and ERK1/2 at both transcriptional and translational levels, suggesting that this miRNA may function as an important regulator of the MAPK signaling pathway. Proinflammatory cytokines consisting of IL-1β, IFN-γ, IL-12p40, IL-17A, and LITAF belonging to Th1 and Th17-type cytokines, were upregulated upon gga-miR-200a-3p overexpression. These findings have enhanced our knowledge of the immune function of gga-miR-200a-3p mediating the chicken immune response via regulation of the MAPK signaling pathway and indicate that this miRNA may serve as an important biomarker of diseases in domestic animals. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

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Section: Discussionmentioning

confidence: 65%

MicroRNA gga-miR-200a-3p modulates immune response via MAPK signaling pathway in chicken afflicted with necrotic enteritis

Pham

Ban

Lee

et al. 2020

Vet Res

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“…Previous research has shown that JCPyV infection induces phosphorylation of ERK1/2 at early time-points during viral infection, occurring at 15 min post-infection [18,24,44]. Activation of ERK1/2 is facilitated directly through dual-phosphorylation by MEK during canonical signaling of the MAPK-ERK cascade [27,45].…”

Section: Resultsmentioning

confidence: 99%

“…Capitalizing on endogenous host-cell mechanisms that are responsible for multiple cellular fates is one way that viruses can effectively function with a such limited genetic toolkit. Indeed, many human DNA viruses utilize MAPK-ERK signaling, often to facilitate viral replication, dysregulate the cell-cycle, alter host immune responses, or even promote cell survival [44].…”

Section: Discussionmentioning

confidence: 99%

JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection

DuShane

Mayberry

Wilczek

et al. 2019

IJMS

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JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.

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“…Polyomavirus binding to the host cell surface rapidly activates cell signaling cascades by G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases [ 40 , 41 , 42 , 43 , 44 ]. Here, we surveyed the role of cellular signaling proteins in JCPyV infection and found that shRNA- and siRNA-mediated knockdown of phosphoinositide 3’-kinase (PI3K) γ and the PI3Kγ regulatory subunit 5 (PIK3R5) specifically inhibited infection by JCPyV and JC pseudoviruses.…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide 3′-Kinase γ Facilitates Polyomavirus Infection

Clark

Gee

Albright

et al. 2020

Viruses

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Polyomaviruses are small, non-enveloped DNA tumor viruses that cause serious disease in immunosuppressed people, including progressive multifocal leukoencephalopathy (PML) in patients infected with JC polyomavirus, but the molecular events mediating polyomavirus entry are poorly understood. Through genetic knockdown approaches, we identified phosphoinositide 3′-kinase γ (PI3Kγ) and its regulatory subunit PIK3R5 as cellular proteins that facilitate infection of human SVG-A glial cells by JCPyV. PI3Kα appears less important for polyomavirus infection than PI3Kγ. CRISPR/Cas9-mediated knockout of PIK3R5 or PI3Kγ inhibited infection by authentic JCPyV and by JC pseudovirus. PI3Kγ knockout also inhibited infection by BK and Merkel Cell pseudoviruses, other pathogenic human polyomaviruses, and SV40, an important model polyomavirus. Reintroduction of the wild-type PI3Kγ gene into the PI3Kγ knock-out SVG-A cells rescued the JCPyV infection defect. Disruption of the PI3Kγ pathway did not block binding of JCPyV to cells or virus internalization, implying that PI3Kγ facilitates some intracellular step(s) of infection. These results imply that agents that inhibit PI3Kγ signaling may have a role in managing polyomavirus infections.

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Human DNA Virus Exploitation of the MAPK-ERK Cascade

Cited by 54 publications

References 219 publications

MicroRNA gga-miR-200a-3p modulates immune response via MAPK signaling pathway in chicken afflicted with necrotic enteritis

MicroRNA gga-miR-200a-3p modulates immune response via MAPK signaling pathway in chicken afflicted with necrotic enteritis

JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection

Phosphoinositide 3′-Kinase γ Facilitates Polyomavirus Infection

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