Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes

Lobeck, Inna N.; Donnelly, Bryan; Dupree, Phylicia; Mahé, Maxime M.; McNeal, Monica; Mohanty, Sujit K.; Tiao, Greg

doi:10.1016/j.virol.2016.09.014

Cited by 11 publications

(7 citation statements)

References 55 publications

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“…Interestingly, blocking SOCE in HIEs significantly reduced the Ca 2+ spikes, but the effect was less pronounced than in MA104 cells, suggesting other pathway(s) may exist that support RV-induced Ca 2+ spikes in HIEs. Further, RV can also infect other cell types, including monocytes and macrophages, hepatocytes, cholangiocytes, and enteroendocrine cells, all of which express a different repertoire of Ca 2+ channels 51,54–56 . Thus, characterizing the nature of RV-induced Ca 2+ signaling in these cell types will help elucidate whether these signals are involved in diseases caused by RV.…”

Section: Discussionmentioning

confidence: 99%

Rotavirus Calcium Dysregulation Manifests as Dynamic Calcium Signaling in the Cytoplasm and Endoplasmic Reticulum

Chang‐Graham¹,

Perry²,

Strtak³

et al. 2019

Sci Rep

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Like many viruses, rotavirus (RV) dysregulates calcium homeostasis by elevating cytosolic calcium ([Ca 2+ ]cyt) and decreasing endoplasmic reticulum (ER) stores. While an overall, monophasic increase in [Ca 2+ ]cyt during RV infection has been shown, the nature of the RV-induced aberrant calcium signals and how they manifest over time at the single-cell level have not been characterized. Thus, we generated cell lines and human intestinal enteroids (HIEs) stably expressing cytosolic and/or ER-targeted genetically-encoded calcium indicators to characterize calcium signaling throughout RV infection by time-lapse imaging. We found that RV induces highly dynamic [Ca 2+ ]cyt signaling that manifest as hundreds of discrete [Ca 2+ ]cyt spikes, which increase during peak infection. Knockdown of nonstructural protein 4 (NSP4) attenuates the [Ca 2+ ]cyt spikes, consistent with its role in dysregulating calcium homeostasis. RV-induced [Ca 2+ ]cyt spikes were primarily from ER calcium release and were attenuated by inhibiting the store-operated calcium entry (SOCE) channel Orai1. RV-infected HIEs also exhibited prominent [Ca 2+ ]cyt spikes that were attenuated by inhibiting SOCE, underlining the relevance of these [Ca 2+ ]cyt spikes to gastrointestinal physiology and role of SOCE in RV pathophysiology. Thus, our discovery that RV increases [Ca 2+ ]cyt by dynamic calcium signaling, establishes a new, paradigm-shifting understanding of the spatial and temporal complexity of virus-induced calcium signaling.

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Section: Discussionmentioning

confidence: 99%

Rotavirus Calcium Dysregulation Manifests as Dynamic Calcium Signaling in the Cytoplasm and Endoplasmic Reticulum

Chang‐Graham¹,

Perry²,

Strtak³

et al. 2019

Sci Rep

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“…Among the three central members of the MAPK pathway, extracellular signalregulated kinase (ERK) 1/2 and p38 activation play the most important roles in RRV infection of cholangiocytes as they seem to be involved in both viral replication and epithelial injury (69). Further studies revealed that ERK phosphorylation and calcium influx appear to be essential to RRV infection, and RRV's viral protein 6 (VP6) drives ERK phosphorylation (70).…”

Section: Cholangiocyte Immunobiologymentioning

confidence: 99%

Innate Immunity and Pathogenesis of Biliary Atresia

et al. 2020

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Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.

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“…https://doi.org/10.1101/562421 doi: bioRxiv preprint Rhesus and group A rotaviruses also activate MAPK/ERK pathway to facilitate viral replication 338 and viral uncoating, respectively(66, 67). https://doi.org/10.1101/562421 doi: bioRxiv preprint Rhesus and group A rotaviruses also activate MAPK/ERK pathway to facilitate viral replication 338 and viral uncoating, respectively(66, 67).…”

mentioning

confidence: 99%

Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway

Kundlacz

Pourcelot

Fablet

et al. 2019

Preprint

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26Bluetongue virus (BTV) is an arbovirus transmitted by blood-feeding midges to a wide 27 range of wild and domestic ruminants. In this report, we showed that BTV, through its virulence 28 non-structural protein NS3 (BTV-NS3), is able to activate the MAPK/ERK pathway. In 29 response to growth factors, the MAPK/ERK pathway activates cell survival, differentiation, 30 proliferation and protein translation but can also lead to the production of several inflammatory 31 cytokines. By combining immunoprecipitation of BTV-NS3 and mass spectrometry analysis 32 from both BTV-infected and NS3-transfected cells, we identified the serine/threonine-protein 33 kinase B-Raf (BRAF), a crucial player of the MAPK/ERK pathway, as a new cellular interactor 34 of BTV-NS3. BRAF silencing led to a significant decrease of the MAPK/ERK activation by 35 BTV supporting a model where BTV-NS3 interacts with BRAF to activate this signaling 36 cascade. Furthermore, the intrinsic ability of BTV-NS3 to bind BRAF and activate the 37 MAPK/ERK pathway is conserved throughout multiple serotypes/strains but appears to be 38 specific to BTV compared to other members of Orbivirus genus. Inhibition of MAPK/ERK 39 pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its 40 own replication. Therefore, the activation of the MAPK/ERK pathway by BTV-NS3 could 41 benefit to BTV replication by promoting its own viral protein synthesis but could also explain 42 the deleterious inflammation associated with tissue damages as already observed in severe cases 43 of BT disease. Altogether, our data provide molecular mechanisms to explain the role of BTV-44 NS3 as a virulence factor and determinant of pathogenesis. 45 author/funder. All rights reserved. No reuse allowed without permission. Importance 46 47Bluetongue Virus (BTV) is responsible of the non-contagious arthropod-borne disease 48 Bluetongue (BT) transmitted to ruminants by blood-feeding midges. Despite the fact that BTV 49 has been extensively studied, we still have little understanding of the molecular determinants 50 of BTV virulence. In this report, we found that the virulence protein NS3 interacts with BRAF, 51a key component of the MAPK/ERK pathway. In response to growth factors, this pathway 52 promotes cell survival, increases protein translation but also contributes to the production of 53 inflammatory cytokines. We showed that BTV-NS3 enhances the MAPK/ERK pathway and 54 this activation is BRAF-dependent. Our results demonstrate, at the molecular level, how a 55 single virulence factor has evolved to target a cellular function to ensure its viral replication. 56On the other hand, our findings could also explain the deleterious inflammation associated with 57 tissue damages as already observed in severe cases of BT disease. 58 author/funder. All rights reserved. No reuse allowed without permission.

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Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes

Cited by 11 publications

References 55 publications

Rotavirus Calcium Dysregulation Manifests as Dynamic Calcium Signaling in the Cytoplasm and Endoplasmic Reticulum

Rotavirus Calcium Dysregulation Manifests as Dynamic Calcium Signaling in the Cytoplasm and Endoplasmic Reticulum

Innate Immunity and Pathogenesis of Biliary Atresia

Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway

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