scholarly journals Antagonism of STAT3 signalling by Ebola virus

2021 ◽  
Vol 17 (6) ◽  
pp. e1009636
Author(s):  
Angela R. Harrison ◽  
Shawn Todd ◽  
Megan Dearnley ◽  
Cassandra T. David ◽  
Diane Green ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Molecular Mechanisms ◽  
Ebola Virus ◽  
Cell Physiology ◽  
Nuclear Trafficking ◽  
Signal Transducers ◽  
Host Interactions ◽  
Ebov Infection ◽  
Interferon Signalling ◽  
Stat3 Signalling

Many viruses target signal transducers and activators of transcription (STAT) 1 and 2 to antagonise antiviral interferon signalling, but targeting of signalling by other STATs/cytokines, including STAT3/interleukin 6 that regulate processes important to Ebola virus (EBOV) haemorrhagic fever, is poorly defined. We report that EBOV potently inhibits STAT3 responses to interleukin-6 family cytokines, and that this is mediated by the interferon-antagonist VP24. Mechanistic analysis indicates that VP24 effects a unique strategy combining distinct karyopherin-dependent and karyopherin-independent mechanisms to antagonise STAT3-STAT1 heterodimers and STAT3 homodimers, respectively. This appears to reflect distinct mechanisms of nuclear trafficking of the STAT3 complexes, revealed for the first time by our analysis of VP24 function. These findings are consistent with major roles for global inhibition of STAT3 signalling in EBOV infection, and provide new insights into the molecular mechanisms of STAT3 nuclear trafficking, significant to pathogen-host interactions, cell physiology and pathologies such as cancer.

scholarly journals Antagonism of STAT3 signalling by Ebola virus

2020 ◽  
Author(s):  
Angela R. Harrison ◽  
Megan Dearnley ◽  
Shawn Todd ◽  
Diane Green ◽  
Glenn A. Marsh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ebola Virus ◽  
Significant Risk ◽  
Disease Outbreaks ◽  
Case Fatality ◽  
Cell Physiology ◽  
Haemorrhagic Fever ◽  
Nuclear Trafficking ◽  
Ebov Infection ◽  
Stat3 Signalling

AbstractMany viruses target signal transducers and activators of transcription (STAT) 1 and 2 to antagonise antiviral interferon (IFN) signalling, but targeting of signalling by other STATs/cytokines, including STAT3/interleukin (IL-) 6 that regulate processes important to Ebola virus (EBOV) haemorrhagic fever, is poorly defined. We report that EBOV potently inhibits STAT3 responses to IL-6 family cytokines, and that this is mediated by the IFN-antagonist VP24. Mechanistic analysis indicates that VP24 effects a unique strategy combining distinct karyopherin-dependent and karyopherin-independent mechanisms to antagonise STAT3-STAT1 heterodimers and STAT3 homodimers, respectively. This appears to reflect distinct mechanisms of nuclear trafficking of the STAT3 complexes, revealed for the first time by our analysis of VP24 function. These findings are consistent with major roles for global inhibition of STAT3 signalling in EBOV infection, and provide new insights into the molecular mechanisms of STAT3 nuclear trafficking, significant to pathogen-host interactions, cell physiology and pathologies such as cancer.Author summaryEbola virus (EBOV) continues to pose a significant risk to human health globally, causing ongoing disease outbreaks with case-fatality rates between 40 and 60%. Suppression of immune responses is a critical component of EBOV haemorrhagic fever, but understanding of EBOV impact on signalling by cytokines other than interferon is limited. We find that infectious EBOV inhibits interleukin-6 cytokine signalling via antagonism of STAT3. The antagonistic strategy uniquely combines two distinct mechanisms, which appear to reflect differing nuclear trafficking mechanisms of critical STAT3 complexes. This provides fundamental insights into the mechanisms of pathogenesis of a lethal virus, and biology of STAT3, a critical player in immunity, development, growth and cancer.

scholarly journals The power to reduce: pyridine nucleotides – small molecules with a multitude of functions

2007 ◽  
Vol 402 (2) ◽  
pp. 205-218 ◽  
Author(s):  
Nadine Pollak ◽  
Christian Dölle ◽  
Mathias Ziegler
Keyword(s):  
Molecular Mechanisms ◽  
Calcium Signalling ◽  
Reduced Form ◽  
Cell Physiology ◽  
Pyridine Nucleotides ◽  
Critical Function ◽  
Signal Transducers ◽  
Regulatory Pathways ◽  
Dependent Protein ◽  
Cellular Defence

The pyridine nucleotides NAD and NADP play vital roles in metabolic conversions as signal transducers and in cellular defence systems. Both coenzymes participate as electron carriers in energy transduction and biosynthetic processes. Their oxidized forms, NAD+ and NADP+, have been identified as important elements of regulatory pathways. In particular, NAD+ serves as a substrate for ADP-ribosylation reactions and for the Sir2 family of NAD+-dependent protein deacetylases as well as a precursor of the calcium mobilizing molecule cADPr (cyclic ADP-ribose). The conversions of NADP+ into the 2′-phosphorylated form of cADPr or to its nicotinic acid derivative, NAADP, also result in the formation of potent intracellular calcium-signalling agents. Perhaps, the most critical function of NADP is in the maintenance of a pool of reducing equivalents which is essential to counteract oxidative damage and for other detoxifying reactions. It is well known that the NADPH/NADP+ ratio is usually kept high, in favour of the reduced form. Research within the past few years has revealed important insights into how the NADPH pool is generated and maintained in different subcellular compartments. Moreover, tremendous progress in the molecular characterization of NAD kinases has established these enzymes as vital factors for cell survival. In the present review, we summarize recent advances in the understanding of the biosynthesis and signalling functions of NAD(P) and highlight the new insights into the molecular mechanisms of NADPH generation and their roles in cell physiology.

scholarly journals Less Is More: Ebola Virus Surface Glycoprotein Expression Levels Regulate Virus Production and Infectivity

2014 ◽  
Vol 89 (2) ◽  
pp. 1205-1217 ◽  
Author(s):  
Gopi S. Mohan ◽  
Ling Ye ◽  
Wenfang Li ◽  
Ana Monteiro ◽  
Xiaoqian Lin ◽  
...  
Keyword(s):  
Rna Editing ◽  
Ebola Virus ◽  
Virus Production ◽  
Surface Glycoprotein ◽  
Cell Physiology ◽  
Virus Infectivity ◽  
Virus Surface ◽  
Expression Levels ◽  
Less Is More ◽  
Ebov Infection

ABSTRACTThe Ebola virus (EBOV) surface glycoprotein (GP1,2) mediates host cell attachment and fusion and is the primary target for host neutralizing antibodies. Expression of GP1,2at high levels disrupts normal cell physiology, and EBOV uses an RNA-editing mechanism to regulate expression of the GP gene. In this study, we demonstrate that high levels of GP1,2expression impair production and release of EBOV virus-like particles (VLPs) as well as infectivity of GP1,2-pseudotyped viruses. We further show that this effect is mediated through two mechanisms. First, high levels of GP1,2expression reduce synthesis of other proteins needed for virus assembly. Second, viruses containing high levels of GP1,2are intrinsically less infectious, possibly due to impaired receptor binding or endosomal processing. Importantly, proteolysis can rescue the infectivity of high-GP1,2-containing viruses. Taken together, our findings indicate that GP1,2expression levels have a profound effect on factors that contribute to virus fitness and that RNA editing may be an important mechanism employed by EBOV to regulate GP1,2expression in order to optimize virus production and infectivity.IMPORTANCEThe Ebola virus (EBOV), as well as other members of theFiloviridaefamily, causes severe hemorrhagic fever that is highly lethal, with up to 90% mortality. The EBOV surface glycoprotein (GP1,2) plays important roles in virus infection and pathogenesis, and its expression is tightly regulated by an RNA-editing mechanism during virus replication. Our study demonstrates that the level of GP1,2expression profoundly affects virus particle production and release and uncovers a new mechanism by which Ebola virus infectivity is regulated by the level of GP1,2expression. These findings extend our understanding of EBOV infection and replication in adaptation of host environments, which will aid the development of countermeasures against EBOV infection.

scholarly journals Feedback Regulation of O-GlcNAc Transferase through Translation Control to Maintain Intracellular O-GlcNAc Homeostasis

2021 ◽  
Vol 22 (7) ◽  
pp. 3463
Author(s):  
Chia-Hung Lin ◽  
Chen-Chung Liao ◽  
Mei-Yu Chen ◽  
Teh-Ying Chou
Keyword(s):  
Molecular Mechanisms ◽  
Mrna Level ◽  
Feedback Regulation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Cell Physiology ◽  
Hydroxyl Groups ◽  
Post Translational Modification ◽  
Translation Control ◽  
Glcnac Transferase

Protein O-GlcNAcylation is a dynamic post-translational modification involving the attachment of N-acetylglucosamine (GlcNAc) to the hydroxyl groups of Ser/Thr residues on numerous nucleocytoplasmic proteins. Two enzymes are responsible for O-GlcNAc cycling on substrate proteins: O-GlcNAc transferase (OGT) catalyzes the addition while O-GlcNAcase (OGA) helps the removal of GlcNAc. O-GlcNAcylation modifies protein functions; therefore, dysregulation of O-GlcNAcylation affects cell physiology and contributes to pathogenesis. To maintain homeostasis of cellular O-GlcNAcylation, there exists feedback regulation of OGT and OGA expression responding to fluctuations of O-GlcNAc levels; yet, little is known about the molecular mechanisms involved. In this study, we investigated the O-GlcNAc-feedback regulation of OGT and OGA expression in lung cancer cells. Results suggest that, upon alterations in O-GlcNAcylation, the regulation of OGA expression occurs at the mRNA level and likely involves epigenetic mechanisms, while modulation of OGT expression is through translation control. Further analyses revealed that the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) contributes to the downregulation of OGT induced by hyper-O-GlcNAcylation; the S5A/S6A O-GlcNAcylation-site mutant of 4E-BP1 cannot support this regulation, suggesting an important role of O-GlcNAcylation. The results provide additional insight into the molecular mechanisms through which cells may fine-tune intracellular O-GlcNAc levels to maintain homeostasis.

scholarly journals The Function of the PRRSV–Host Interactions and Their Effects on Viral Replication and Propagation in Antiviral Strategies

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 364
Author(s):  
Jun Ma ◽  
Lulu Ma ◽  
Meiting Yang ◽  
Wei Wu ◽  
Wenhai Feng ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Rna Virus ◽  
Economic Losses ◽  
Respiratory Syndrome Virus ◽  
Swine Industry ◽  
Live Virus ◽  
Virus Challenge ◽  
Host Interactions

Porcine reproductive and respiratory syndrome virus (PRRSV) affects the global swine industry and causes disastrous economic losses each year. The genome of PRRSV is an enveloped single-stranded positive-sense RNA of approximately 15 kb. The PRRSV replicates primarily in alveolar macrophages of pig lungs and lymphatic organs and causes reproductive problems in sows and respiratory symptoms in piglets. To date, studies on how PRRSV survives in the host, the host immune response against viral infections, and pathogenesis, have been reported. PRRSV vaccines have been developed, including inactive virus, modified live virus, attenuated live vaccine, DNA vaccine, and immune adjuvant vaccines. However, there are certain problems with the durability and effectiveness of the licensed vaccines. Moreover, the high variability and fast-evolving populations of this RNA virus challenge the design of PRRSV vaccines, and thus effective vaccines against PRRSV have not been developed successfully. As is well known, viruses interact with the host to escape the host’s immune response and then replicate and propagate in the host, which is the key to virus survival. Here, we review the complex network and the mechanism of PRRSV–host interactions in the processes of virus infection. It is critical to develop novel antiviral strategies against PRRSV by studying these host–virus interactions and structures to better understand the molecular mechanisms of PRRSV immune escape.

scholarly journals The role of interleukin‑6‑STAT3 signalling in glioblastoma (Review)

2018 ◽  
Author(s):  
Alice West ◽  
Vanessa Tsui ◽  
Stanley Stylli ◽  
Hong Nguyen ◽  
Andrew Morokoff ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Stat3 Signalling

scholarly journals In vivo single-cell profiling of lncRNAs during Ebola virus infection

2022 ◽  
Author(s):  
Luisa Santus ◽  
Raquel García-Pérez ◽  
Maria Sopena-Rios ◽  
Aaron E Lin ◽  
Gordon C Adams ◽  
...  
Keyword(s):  
Viral Infection ◽  
Single Cell ◽  
Ebola Virus ◽  
Cell Type ◽  
Protein Coding ◽  
Expression Variation ◽  
Lncrna Expression ◽  
Ebov Infection ◽  
Cell Type Specific

Long non-coding RNAs (lncRNAs) are pivotal mediators of systemic immune response to viral infection, yet most studies concerning their expression and functions upon immune stimulation are limited to in vitro bulk cell populations. This strongly constrains our understanding of how lncRNA expression varies at single-cell resolution, and how their cell-type specific immune regulatory roles may differ compared to protein-coding genes. Here, we perform the first in-depth characterization of lncRNA expression variation at single-cell resolution during Ebola virus (EBOV) infection in vivo. Using bulk RNA-sequencing from 119 samples and 12 tissue types, we significantly expand the current macaque lncRNA annotation. We then profile lncRNA expression variation in immune circulating single-cells during EBOV infection and find that lncRNAs' expression in fewer cells is a major differentiating factor from their protein-coding gene counterparts. Upon EBOV infection, lncRNAs present dynamic and mostly cell-type specific changes in their expression profiles especially in monocytes, the main cell type targeted by EBOV. Such changes are associated with gene regulatory modules related to important innate immune responses such as interferon response and purine metabolism. Within infected cells, several lncRNAs have positively and negatively correlated expression with viral load, suggesting that expression of some of these lncRNAs might be directly hijacked by EBOV to attack host cells. This study provides novel insights into the roles that lncRNAs play in the host response to acute viral infection and paves the way for future lncRNA studies at single-cell resolution.

scholarly journals Modeling acute ethanol-induced impairment with gastric organoids

2021 ◽  
Author(s):  
Wanjuan Wang ◽  
Ying Zhao ◽  
Zeqi Su ◽  
Fuhao Chu ◽  
Tao Li ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Molecular Mechanisms ◽  
Apical Membrane ◽  
Parietal Cells ◽  
Basic Medium ◽  
Cell Physiology ◽  
Membrane Cytoskeleton ◽  
Acute Ethanol ◽  
Functional Consequences ◽  
Gastric Parietal Cells

Abstract Background: Ethanol has been linked to atrophic gastritis and gastric carcinoma. Although it is well known that ethanol can result in hypochlorhydria, the molecular mechanisms underlying this phenomenon remain poorly understood.Results: Here we used gastric organoids to show that ethanol permeabilized the apical membrane of gastric parietal cells and induced ezrin hypochlorhydria. The functional consequences of ethanol on parietal cell physiology were studied using organoids. Gastric organoids were pre-incubated in the basic medium or with EGTA or E64 , and incubated at 37℃ in either medium alone, or medium containing 6% ethanol. We assessed ezrin proteolysis. Ethanol permeabilization induced activation of calpainⅠand subsequent proteolysis of ezrin, which resulted in the liberation of ezrin from the apical membrane of the parietal cells. Significantly, expression of calpain-resistant ezrin restored the functional activity of parietal cells in the presence of ethanol.Conclusion: Taken together, our data indicated that ethanol disrupted the apical membrane-cytoskeleton interactions in gastric parietal cells and thereby caused hypochlorhydria.

scholarly journals Enhancement of Ebola virus infection by seminal amyloid fibrils

2018 ◽  
Vol 115 (28) ◽  
pp. 7410-7415 ◽  
Author(s):  
Stephen M. Bart ◽  
Courtney Cohen ◽  
John M. Dye ◽  
James Shorter ◽  
Paul Bates
Keyword(s):  
Cell Lines ◽  
Ebola Virus ◽  
Amyloid Fibrils ◽  
Sexual Transmission ◽  
Fluid Phase ◽  
Infectious Individual ◽  
Transmission Potential ◽  
Western Africa ◽  
Ebov Infection

The 2014 western Africa Ebola virus (EBOV) epidemic was unprecedented in magnitude, infecting over 28,000 and causing over 11,000 deaths. During this outbreak, multiple instances of EBOV sexual transmission were reported, including cases where the infectious individual had recovered from EBOV disease months before transmission. Potential human host factors in EBOV sexual transmission remain unstudied. Several basic seminal amyloids, most notably semen-derived enhancer of viral infection (SEVI), enhance in vitro infection by HIV and several other viruses. To test the ability of these peptides to enhance EBOV infection, viruses bearing the EBOV glycoprotein (EboGP) were preincubated with physiological concentrations of SEVI before infection of physiologically relevant cell lines and primary cells. Preincubation with SEVI significantly increased EboGP-mediated infectivity and replication in epithelium- and monocyte-derived cell lines. This enhancement was dependent upon amyloidogenesis and positive charge, and infection results were observed with both viruses carrying EboGP and authentic EBOV as well as with semen. SEVI enhanced binding of virus to cells and markedly increased its subsequent internalization. SEVI also stimulated uptake of a fluid phase marker by macropinocytosis, a critical mechanism by which cells internalize EBOV. We report a previously unrecognized ability of SEVI and semen to significantly alter viral physical properties critical for transmissibility by increasing the stability of EboGP-bearing recombinant viruses during incubation at elevated temperature and providing resistance to desiccation. Given the potential for EBOV sexual transmission to spark new transmission chains, these findings represent an important interrogation of factors potentially important for this EBOV transmission route.

scholarly journals Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Punya Shrivastava-Ranjan ◽  
Mike Flint ◽  
Éric Bergeron ◽  
Anita K. McElroy ◽  
Payel Chatterjee ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Statin Treatment ◽  
Ebola Virus Disease ◽  
Health Concern ◽  
Virus Infectivity ◽  
Viral Glycoprotein ◽  
Antiviral Effects ◽  
Ebov Infection ◽  
Glycoprotein Processing

ABSTRACTEbola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013–2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infectionin vitro. Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.IMPORTANCETreatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

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