scholarly journals The Atypical Kinase RIOK3 Limits RVFV Propagation and Is Regulated by Alternative Splicing

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 367
Author(s):  
Katherine E. Havranek ◽  
Luke Adam White ◽  
Thomas C. Bisom ◽  
Jean-Marc Lanchy ◽  
J. Stephen Lodmell
Keyword(s):  
Alternative Splicing ◽  
Mammalian Cells ◽  
Rift Valley Fever Virus ◽  
Critical Role ◽  
Fine Tuning ◽  
Interferon Response ◽  
Type I ◽  
Interferon Signaling ◽  
Valley Fever ◽  
Alternatively Spliced

In recent years, transcriptome profiling studies have identified changes in host splicing patterns caused by viral invasion, yet the functional consequences of the vast majority of these splicing events remain uncharacterized. We recently showed that the host splicing landscape changes during Rift Valley fever virus MP-12 strain (RVFV MP-12) infection of mammalian cells. Of particular interest, we observed that the host mRNA for Rio Kinase 3 (RIOK3) was alternatively spliced during infection. This kinase has been shown to be involved in pattern recognition receptor (PRR) signaling mediated by RIG-I like receptors to produce type-I interferon. Here, we characterize RIOK3 as an important component of the interferon signaling pathway during RVFV infection and demonstrate that RIOK3 mRNA expression is skewed shortly after infection to produce alternatively spliced variants that encode premature termination codons. This splicing event plays a critical role in regulation of the antiviral response. Interestingly, infection with other RNA viruses and transfection with nucleic acid-based RIG-I agonists also stimulated RIOK3 alternative splicing. Finally, we show that specifically stimulating alternative splicing of the RIOK3 transcript using a morpholino oligonucleotide reduced interferon expression. Collectively, these results indicate that RIOK3 is an important component of the mammalian interferon signaling cascade and its splicing is a potent regulatory mechanism capable of fine-tuning the host interferon response.

scholarly journals The Dynamic Interface of Viruses with STATs

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Angela R. Harrison ◽  
Gregory W. Moseley
Keyword(s):  
Critical Role ◽  
Viral Gene Expression ◽  
Interferon Response ◽  
Viral Gene ◽  
Type I ◽  
Interferon Signaling ◽  
Dynamic Interface ◽  
Cellular Factors ◽  
Targeting Signal

ABSTRACT Viruses commonly antagonize the antiviral type I interferon response by targeting signal transducer and activator of transcription 1 (STAT1) and STAT2, key mediators of interferon signaling. Other STAT family members mediate signaling by diverse cytokines important to infection, but their relationship with viruses is more complex. Importantly, virus-STAT interaction can be antagonistic or stimulatory depending on diverse viral and cellular factors. While STAT antagonism can suppress immune pathways, many viruses promote activation of specific STATs to support viral gene expression and/or produce cellular conditions conducive to infection. It is also becoming increasingly clear that viruses can hijack noncanonical STAT functions to benefit infection. For a number of viruses, STAT function is dynamically modulated through infection as requirements for replication change. Given the critical role of STATs in infection by diverse viruses, the virus-STAT interface is an attractive target for the development of antivirals and live-attenuated viral vaccines. Here, we review current understanding of the complex and dynamic virus-STAT interface and discuss how this relationship might be harnessed for medical applications.

scholarly journals A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

2009 ◽  
Vol 206 (9) ◽  
pp. 1899-1911 ◽  
Author(s):  
Sarah M. McWhirter ◽  
Roman Barbalat ◽  
Kathryn M. Monroe ◽  
Mary F. Fontana ◽  
Mamoru Hyodo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Map Kinases ◽  
Second Messenger ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Host Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.

scholarly journals Fine-Tuning of Type I Interferon Response by STAT3

2019 ◽  
Vol 10 ◽  
Author(s):  
Ming-Hsun Tsai ◽  
Li-Mei Pai ◽  
Chien-Kuo Lee
Keyword(s):  
Type I Interferon ◽  
Fine Tuning ◽  
Interferon Response ◽  
Type I

scholarly journals Critical Role for Alpha/Beta and Gamma Interferons in Persistence of Lymphocytic Choriomeningitis Virus by Clonal Exhaustion of Cytotoxic T Cells

2001 ◽  
Vol 75 (18) ◽  
pp. 8407-8423 ◽  
Author(s):  
Rong Ou ◽  
Shenghua Zhou ◽  
Lei Huang ◽  
Demetrius Moskophidis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Interferon Response ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Alpha Beta

ABSTRACT Under conditions of high antigenic load during infection with invasive lymphocytic choriomeningitis virus (LCMV) strains, virus can persist by selective clonal exhaustion of antigen-specific CD8+ T cells. In this work we studied the down-regulation of the virus-specific CD8+-T-cell response during a persistent infection of adult mice, with particular emphasis on the contribution of the interferon response in promoting host defense. Studies were conducted by infecting mice deficient in receptors for type I (alpha/beta interferon [IFN-α/β]), type II (IFN-γ), and both type I and II IFNs with LCMV isolates that vary in their capacity to induce T-cell exhaustion. The main conclusions of this study are as follows. (i) IFNs play a critical role in LCMV infection by reducing viral loads in the initial stages of infection and thus modifying both the extent of CD8+-T-cell exhaustion and the course of infection. The importance of IFNs in this context varies with the biological properties of the LCMV strain. (ii) An inverse correlation exists between antigen persistence and responsiveness of virus-specific CD8+ T cells. This results in distinct programs of activation or tolerance (functional unresponsiveness and/or physical elimination of antigen-specific cells) during acute and chronic virus infections, respectively. (iii) A successful immune response associated with definitive viral clearance requires an appropriate balance between cellular and humoral components of the immune system. We discuss the role of IFNs in influencing virus-specific T cells that determine the outcome of persistent infections.

scholarly journals NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

2009 ◽  
Vol 5 (7) ◽  
pp. e1000500 ◽  
Author(s):  
Amit K. Pandey ◽  
Yibin Yang ◽  
Zhaozhao Jiang ◽  
Sarah M. Fortune ◽  
Francois Coulombe ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type I Interferon ◽  
Critical Role ◽  
Interferon Response ◽  
Type I

scholarly journals The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice Not Related with a Type-I IFN Antagonistic Phenotype

2021 ◽  
Author(s):  
Belén Borrego ◽  
Sandra Moreno ◽  
Nuria de la Losa ◽  
Friedemann Weber ◽  
Alejandro Brun
Keyword(s):  
Amino Acid ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Single Amino Acid ◽  
Economic Losses ◽  
Type I ◽  
Valley Fever

Rift valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes an important disease in ruminants, with great economic losses. The infection can be also transmitted to humans; therefore it is considered a major threat to both human and animal health. In a previous work, we described a novel RVFV variant selected in cell culture in the presence of the antiviral agent favipiravir that was highly attenuated in vivo. This variant displayed 24 amino acid substitutions in different viral proteins when compared to its parental viral strain, two of them located in the NSs protein that is known to be the major virulence factor of RVFV. By means of a reverse genetics system, in this work we have analyzed the effect that one of these substitutions, P82L, has in viral attenuation in vivo. Rescued viruses carrying this single amino acid change were clearly attenuated in BALB/c mice while their growth in an IFN-competent cell line as well as the production of IFN-β did not seem to be affected. However, the pattern of nuclear NSs accumulation was modified in cells infected with the mutant viruses. These results unveil a new RVFV virulence marker highlighting the multiple ways of NSs protein to modulate viral infectivity.

scholarly journals Ebola virus infection induces a type I interferon response and the shutdown of key liver functions in human iPSC-derived hepatocytes

2021 ◽  
Author(s):  
Whitney Manhart ◽  
Liliana Mancio ◽  
Ellen Suder ◽  
Carlos Villacorta-Martin ◽  
Jonathan Lindstrom-Vautrin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Ebola Virus ◽  
Interferon Response ◽  
Type I ◽  
Interferon Signaling ◽  
Liver Functions ◽  
Ebov Infection ◽  
Transcriptomic Changes ◽  
Human Ipsc ◽  
Ebola Virus Infection

Abstract Liver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the intrinsic response to infection in human hepatocytes and their contribution to the observed inflammatory response. Here, we present an iPSC-derived hepatocyte platform to define the hepato-intrinsic response to EBOV infection. Transcriptomics analysis revealed a delayed host response with minimal transcriptomic changes at one day post infection (dpi) followed by a general downregulation of genes associated with hepatic functions and upregulation of interferon signaling at two and three dpi. Using RNA-FISH, we showed at single cell resolution that IFNβ and CXCL10 were mainly expressed in bystander cells or cells with weak EBOV mRNA signal intensity. We did not observe an inflammatory signature at any timepoint. In conclusion, iPSC-derived hepatocytes are an immune competent platform to study intrinsic responses to EBOV infection that have not been observed in EBOV-infected hepatocarcinoma cell lines.

scholarly journals Comprehensive Identification and Alternative Splicing of Microexons in Drosophila

2021 ◽  
Vol 12 ◽  
Author(s):  
Ting-Lin Pang ◽  
Zhan Ding ◽  
Shao-Bo Liang ◽  
Liang Li ◽  
Bei Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Sex Determination ◽  
Rna Splicing ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Pathway Gene ◽  
Mrna Transcripts ◽  
Bioinformatic Tool ◽  
Alternatively Spliced

Interrupted exons in the pre-mRNA transcripts are ligated together through RNA splicing, which plays a critical role in the regulation of gene expression. Exons with a length ≤ 30 nt are defined as microexons that are unique in identification. However, microexons, especially those shorter than 8 nt, have not been well studied in many organisms due to difficulties in mapping short segments from sequencing reads. Here, we analyzed mRNA-seq data from a variety of Drosophila samples with a newly developed bioinformatic tool, ce-TopHat. In addition to the Flybase annotated, 465 new microexons were identified. Differentially alternatively spliced (AS) microexons were investigated between the Drosophila tissues (head, body, and gonad) and genders. Most of the AS microexons were found in the head and two AS microexons were identified in the sex-determination pathway gene fruitless.

scholarly journals Multi-level regulation of PKCδI alternative splicing by lithium chloride

2020 ◽  
Author(s):  
Deena Bader ◽  
Rekha S. Patel ◽  
Ashley Lui ◽  
Chetna Thawani ◽  
Rea Rupani ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Lithium Chloride ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Fine Tuning ◽  
Serine Threonine Kinase ◽  
Rna Immunoprecipitation ◽  
Alternatively Spliced ◽  
Licl Treatment ◽  
Lncrna Neat1

Lithium chloride (LiCl) is commonly used in treatment of mood disorders, however its usage leads to weight gain which promotes metabolic disorders. Protein Kinase C delta (PKCδ), a serine/threonine kinase, is alternatively spliced to PKCδI and PKCδII in 3T3L1 cells. We previously demonstrated that PKCδI is the predominantly expressed isoform in 3T3L1 pre-adipocytes. Here, we demonstrate that LiCl treatment decreases PKCδI levels, increases formation of lipid droplets and increases oxidative stress. Hence, we investigated the molecular mechanisms underlying the regulation of PKCδI alternative splicing by LiCl. We previously demonstrated that the splice factor SFRS10 is essential for PKCδI splicing. Our results demonstrate that GSK3ß phosphorylates SFRS10 and SFRS10 is in a complex with long noncoding RNA NEAT1 to promote PKCδI splicing. Using PKCδ splicing minigene and RNA-immunoprecipitation assays, our results demonstrate that upon LiCl treatment, NEAT1 levels are reduced, GSK3ß activity is inhibited and SFRS10 phosphorylation is decreased which leads to decreased expression of PKCδI. Integration of the GSK3ß signaling pathway with the ribonucleoprotein complex of lncRNA NEAT1 and SFRS10 enables fine tuning of PKCδI expression during adipogenesis. Knowledge of the molecular pathways impacted by LiCl provide an understanding of the ascent of obesity as a comorbidity in disease management.

The mRNA encoding TAFI is alternatively spliced in different cell types and produces intracellular forms of the protein lacking TAFIa activity

2013 ◽  
Vol 109 (06) ◽  
pp. 1033-1044 ◽  
Author(s):  
Joellen H. H. Lin ◽  
Dragana Novakovic ◽  
Christina M. Rizzo ◽  
Branislava Zagorac ◽  
Mathieu Garand ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Recombinant Expression ◽  
Cell Types ◽  
Coagulation Cascade ◽  
Peptidase Activity ◽  
Peripheral Blood Mononuclear ◽  
Mrna Variant ◽  
Alternatively Spliced

SummaryTAFI (thrombin-activatable fibrinolysis inhibitor) is a pro-carboxypeptidase, encoded by the CPB2 gene in humans that links the coagulation cascade to fibrinolysis and inflammation. The liver is the main source for plasma TAFI, and TAFI expression has been documented in platelets and monocyte-derived macrophages. A recent study reported an alternatively spliced CPB2 mRNA variant lacking exon 7 (Δ7) in HepG2 cells and liver. Another study identified a CPB2 mRNA variant lacking exon 7 and a 52 bp deletion in exon 11 (Δ7+11) in human hippocampus. We have examined alternative splicing of CPB2 mRNA in various cell types by RT-PCR and have assessed the functional properties of TAFI variants encoded by these transcripts by recombinant expression in mammalian cells. We identified the Δ7 exon skipping event in liver, Dami megakaryoblasts, THP-1-derived macrophages, peripheral blood mononuclear cells, platelets, testis, cerebellum, and SH-SY5Y neuroblastoma cells. The Δ11 alternative splicing event was notably absent in liver cells. We also detected a novel exon Δ7+8 skipping event in liver and megakaryocytes. Of note, we detected non-alternatively spliced CPB2 transcripts in brain tissues, suggesting the expression of full-length TAFI in brain. Experiments using cultured mammalian cells transfected with wild-type CPB2-, Δ7-, Δ7+11 -, and_Δ11 -cDNA revealed that alternatively spliced TAFI is stored inside the cells, cannot be activated by thrombin-thrombomodulin, and does not have TAFIa activity. The alternative splicing events clearly do not give rise to a secreted protein with basic carboxy-peptidase activity, but the intracellular forms may possess novel functions related to intracellular proteolysis.

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