scholarly journals PP2A Facilitates Porcine Reproductive and Respiratory Syndrome Virus Replication by Deactivating irf3 and Limiting Type I Interferon Production

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 948 ◽  
Author(s):  
Jiayu Xu ◽  
Lu Zhang ◽  
Yunfei Xu ◽  
He Zhang ◽  
Junxin Gao ◽  
...  
Keyword(s):  
Virus Infection ◽  
Therapeutic Target ◽  
Type I Interferon ◽  
Negative Regulator ◽  
Host Cells ◽  
Respiratory Syndrome Virus ◽  
Target Cells ◽  
Type I ◽  
Dependent Manner ◽  
Pp2a Activity

Protein phosphatase 2A (PP2A), a major serine/threonine phosphatase in mammalian cells, is known to regulate the kinase-driven intracellular signaling pathways. Emerging evidences have shown that the PP2A phosphatase functions as a bona-fide therapeutic target for anticancer therapy, but it is unclear whether PP2A affects a porcine reproductive and respiratory syndrome virus infection. In the present study, we demonstrated for the first time that inhibition of PP2A activity by either inhibitor or small interfering RNA duplexes in target cells significantly reduced their susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) infection. Further analysis revealed that inhibition of PP2A function resulted in augmented production of type I interferon (IFN). The mechanism is that inhibition of PP2A activity enhances the levels of phosphorylated interferon regulatory factor 3, which activates the transcription of IFN-stimulated genes. Moreover, inhibition of PP2A activity mainly blocked PRRSV replication in the early stage of viral life cycle, after virus entry but before virus release. Using type I IFN receptor 2 specific siRNA in combination with PP2A inhibitor, we confirmed that the effect of PP2A on viral replication within target cells was an interferon-dependent manner. Taken together, these findings demonstrate that PP2A serves as a negative regulator of host cells antiviral responses and provides a novel therapeutic target for virus infection.

scholarly journals Binding of Brucella protein, Bp26, to select extracellular matrix molecules

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Yasmin ElTahir ◽  
Amna Al-Araimi ◽  
Remya R. Nair ◽  
Kaija J. Autio ◽  
Hongmin Tu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Host Cells ◽  
Mouse Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Target Cells ◽  
Type I ◽  
Dependent Manner ◽  
Biolayer Interferometry

Abstract Background Brucella is a facultative intracellular pathogen responsible for zoonotic disease brucellosis. Little is known about the molecular basis of Brucella adherence to host cells. In the present study, the possible role of Bp26 protein as an adhesin was explored. The ability of Brucella protein Bp26 to bind to extracellular matrix (ECM) proteins was determined by enzyme-linked immunosorbent assay (ELISA) and biolayer interferometry (BLI). Results ELISA experiments showed that Bp26 bound in a dose-dependent manner to both immobilized type I collagen and vitronectin. Bp26 bound weakly to soluble fibronectin but did not bind to immobilized fibronectin. No binding to laminin was detected. Biolayer interferometry showed high binding affinity of Bp26 to immobilized type I collagen and no binding to fibronectin or laminin. Mapping of Bp26 antigenic epitopes by biotinylated overlapping peptides spanning the entire sequence of Bp26 using anti Bp26 mouse serum led to the identification of five linear epitopes. Collagen and vitronectin bound to peptides from several regions of Bp26, with many of the binding sites for the ligands overlapping. The strongest binding for anti-Bp26 mouse serum, collagen and vitronectin was to the peptides at the C-terminus of Bp26. Fibronectin did not bind to any of the peptides, although it bound to the whole Bp26 protein. Conclusions Our results highlight the possible role of Bp26 protein in the adhesion process of Brucella to host cells through ECM components. This study revealed that Bp26 binds to both immobilized and soluble type I collagen and vitronectin. It also binds to soluble but not immobilized fibronectin. However, Bp26 does not bind to laminin. These are novel findings that offer insight into understanding the interplay between Brucella and host target cells, which may aid in future identification of a new target for diagnosis and/or vaccine development and prevention of brucellosis.

scholarly journals Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling

2010 ◽  
Vol 6 (7) ◽  
pp. e1001016 ◽  
Author(s):  
Elizabeth J. Faul ◽  
Celestine N. Wanjalla ◽  
Mehul S. Suthar ◽  
Michael Gale ◽  
Christoph Wirblich ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Virus Infection ◽  
Rabies Virus ◽  
Cell Activation ◽  
Type I Interferon ◽  
Type I ◽  
Dependent Manner ◽  
Interferon Production ◽  
Dendritic Cell Activation ◽  
Rabies Virus Infection

scholarly journals Two-Component Regulators ControlhilAExpression by ControllingfimZandhilEExpression within Salmonella enterica Serovar Typhimurium

2014 ◽  
Vol 83 (3) ◽  
pp. 978-985 ◽  
Author(s):  
M. Aaron Baxter ◽  
Bradley D. Jones
Keyword(s):  
Transcriptional Activator ◽  
Negative Regulator ◽  
Host Cells ◽  
Type I ◽  
Dependent Manner ◽  
Content Type ◽  
Regulatory Systems ◽  
Two Component ◽  
Serovar Typhimurium ◽  
Type I Fimbriae

Salmonellae initiate disease through the invasion of host cells within the intestine. This ability to invade requires the coordinated action of numerous genes, many of which are found withinSalmonellapathogenicity island 1 (SPI-1). The key to this process is the ability of the bacteria to respond to the environment, thereby upregulating the necessary genes under optimal conditions. Central to the control of SPI-1 is the transcriptional activatorhilA. Work has identified at least 10 different activators and 8 different repressors responsible for the control ofhilA. We have previously shown thathilEis aSalmonella-specific negative regulator that is able to represshilAexpression and invasion. Additionally,fimZ, a transcriptional activator responsible for the expression of type I fimbriae as well as flagellar genes, has also been implicated in this process.fimZis homologous to response regulators from other two-component regulatory systems, although a sensor for the system has not been identified. ThephoPQandphoBRregulons are both two-component systems that negatively affecthilAexpression, although the mechanism of action has not been determined. Our results show that PhoBR is capable of inducingfimZexpression, whereas PhoPQ does not affectfimZexpression but does upregulatehilEin an FimZ-dependent manner. Therefore, phosphate (sensed by PhoBR) and magnesium (sensed by PhoPQ) levels are important in controllinghilAexpression levels whenSalmonellais in the intestinal environment.

scholarly journals Junín Virus Infection Activates the Type I Interferon Pathway in a RIG-I-Dependent Manner

2012 ◽  
Vol 6 (5) ◽  
pp. e1659 ◽  
Author(s):  
Cheng Huang ◽  
Olga A. Kolokoltsova ◽  
Nadezdha E. Yun ◽  
Alexey V. Seregin ◽  
Allison L. Poussard ◽  
...  
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Type I ◽  
Dependent Manner ◽  
Junin Virus ◽  
Interferon Pathway ◽  
Junín Virus

scholarly journals JMJD6 negatively regulates cytosolic RNA induced antiviral signaling by recruiting RNF5 to promote activated IRF3 K48 ubiquitination

2021 ◽  
Vol 17 (3) ◽  
pp. e1009366
Author(s):  
Wei Zhang ◽  
Qi Wang ◽  
Fan Yang ◽  
Zixiang Zhu ◽  
Yueyue Duan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Rna Virus ◽  
Negative Regulator ◽  
Viral Rna ◽  
Poly I:C ◽  
Type I ◽  
Dependent Manner ◽  
Antiviral Signaling

The negative regulation of antiviral immune responses is essential for the host to maintain homeostasis. Jumonji domain-containing protein 6 (JMJD6) was previously identified with a number of functions during RNA virus infection. Upon viral RNA recognition, retinoic acid-inducible gene-I-like receptors (RLRs) physically interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type-I interferon (IFN-I) production. Here, JMJD6 was demonstrated to reduce type-I interferon (IFN-I) production in response to cytosolic poly (I:C) and RNA virus infections, including Sendai virus (SeV) and Vesicular stomatitis virus (VSV). Genetic inactivation of JMJD6 enhanced IFN-I production and impaired viral replication. Our unbiased proteomic screen demonstrated JMJD6 contributes to IRF3 K48 ubiquitination degradation in an RNF5-dependent manner. Mice with gene deletion of JMJD6 through piggyBac transposon-mediated gene transfer showed increased VSV-triggered IFN-I production and reduced susceptibility to the virus. These findings classify JMJD6 as a negative regulator of the host’s innate immune responses to cytosolic viral RNA.

scholarly journals Bleomycin-Induced Lung Injury Increases Resistance to Influenza Virus Infection in a Type I Interferon-Dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Sang-Uk Seo ◽  
Jae-Hyeon Jeong ◽  
Bum-Seo Baek ◽  
Je-Min Choi ◽  
Youn Soo Choi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Lung Injury ◽  
Inflammatory Cytokine ◽  
Type I Interferon ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Type I ◽  
Dependent Manner ◽  
Infection Period

Acute lung injury (ALI) results in acute respiratory disease that causes fatal respiratory diseases; however, little is known about the incidence of influenza infection in ALI. Using a ALI-mouse model, we investigated the pro-inflammatory cytokine response to ALI and influenza infection. Mice treated with bleomycin (BLM), which induces ALI, were more resistant to influenza virus infection and exhibited higher levels of type I interferon (IFN-I) transcription during the early infection period than that in PBS-treated control mice. BLM-treated mice also exhibited a lower viral burden, reduced pro-inflammatory cytokine production, and neutrophil levels. In contrast, BLM-treated IFN-I receptor 1 (IFNAR1)-knockout mice failed to show this attenuated phenotype, indicating that IFN-I is key to the antiviral response in ALI-induced mice. The STING/TBK1/IRF3 pathway was found to be involved in IFN-I production and the establishment of an antiviral environment in the lung. The depletion of plasmacytoid dendritic cells (pDCs) reduced the effect of BLM treatment against influenza virus infection, suggesting that pDCs are the major source of IFN-I and are crucial for defense against viral infection in BLM-induced lung injury. Overall, this study showed that BLM-mediated ALI in mice induced the release of double-stranded DNA, which in turn potentiated IFN-I-dependent pulmonary viral resistance by activating the STING/TBK1/IRF3 pathway in association with pDCs.

scholarly journals Porcine Epidemic Diarrhea Virus Infection Inhibits Interferon Signaling by Targeted Degradation of STAT1

2016 ◽  
Vol 90 (18) ◽  
pp. 8281-8292 ◽  
Author(s):  
Longjun Guo ◽  
Xiaolei Luo ◽  
Ren Li ◽  
Yunfei Xu ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Porcine Epidemic Diarrhea Virus ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Infection Type ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea

ABSTRACTPorcine epidemic diarrhea virus (PEDV) is a worldwide-distributed alphacoronavirus, but the pathogenesis of PEDV infection is not fully characterized. During virus infection, type I interferon (IFN) is a key mediator of innate antiviral responses. Most coronaviruses develop some strategy for at least partially circumventing the IFN response by limiting the production of IFN and by delaying the activation of the IFN response. However, the molecular mechanisms by which PEDV antagonizes the antiviral effects of interferon have not been fully characterized. Especially, how PEDV impacts IFN signaling components has yet to be elucidated. In this study, we observed that PEDV was relatively resistant to treatment with type I IFN. Western blot analysis showed that STAT1 expression was markedly reduced in PEDV-infected cells and that this reduction was not due to inhibition of STAT1 transcription. STAT1 downregulation was blocked by a proteasome inhibitor but not by an autophagy inhibitor, strongly implicating the ubiquitin-proteasome targeting degradation system. Since PEDV infection-induced STAT1 degradation was evident in cells pretreated with the general tyrosine kinase inhibitor, we conclude that STAT1 degradation is independent of the IFN signaling pathway. Furthermore, we report that PEDV-induced STAT1 degradation inhibits IFN-α signal transduction pathways. Pharmacological inhibition of STAT1 degradation rescued the ability of the host to suppress virus replication. Collectively, these data show that PEDV is capable of subverting the type I interferon response by inducing STAT1 degradation.IMPORTANCEIn this study, we show that PEDV is resistant to the antiviral effect of IFN. The molecular mechanism is the degradation of STAT1 by PEDV infection in a proteasome-dependent manner. This PEDV infection-induced STAT1 degradation contributes to PEDV replication. Our findings reveal a new mechanism evolved by PEDV to circumvent the host antiviral response.

Sign in / Sign up

Export Citation Format

Share Document