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J.Stephen Lodmell
Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT 59812, USA

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Journal article
Published: 26 February 2021 in Viruses
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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.

ACS Style

Katherine Havranek; Luke White; Thomas Bisom; Jean-Marc Lanchy; J. Lodmell. The Atypical Kinase RIOK3 Limits RVFV Propagation and Is Regulated by Alternative Splicing. Viruses 2021, 13, 367 .

AMA Style

Katherine Havranek, Luke White, Thomas Bisom, Jean-Marc Lanchy, J. Lodmell. The Atypical Kinase RIOK3 Limits RVFV Propagation and Is Regulated by Alternative Splicing. Viruses. 2021; 13 (3):367.

Chicago/Turabian Style

Katherine Havranek; Luke White; Thomas Bisom; Jean-Marc Lanchy; J. Lodmell. 2021. "The Atypical Kinase RIOK3 Limits RVFV Propagation and Is Regulated by Alternative Splicing." Viruses 13, no. 3: 367.

Review article
Published: 14 February 2019 in Non-coding RNA Research
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C/D box snoRNAs (SNORDs) are a highly expressed class of non-coding RNAs. Besides their well-established role in rRNA modification, C/D box snoRNAs form protein complexes devoid of fibrillarin and regulate pre-mRNA splicing and polyadenylation of numerous genes. There is an emerging body of evidence for functional interactions between RNA viruses and C/D box snoRNAs. The infectivity of some RNA viruses depends on enzymatically active fibrillarin, and many RNA viral proteins associate with nucleolin or nucleophosmin, suggesting that viruses benefit from their cytosolic accumulation. These interactions are likely reflected by morphological changes in the nucleolus, often leading to relocalization of nucleolar proteins and ncRNAs to the cytosol that are a characteristic feature of viral infections. Knock-down studies have also shown that RNA viruses need specific C/D box snoRNAs for optimal replication, suggesting that RNA viruses benefit from gene expression programs regulated by SNORDs, or that viruses have evolved “new” uses for these humble ncRNAs to advance their prospects during infection.

ACS Style

Stefan Stamm; J. Stephen Lodmell. C/D box snoRNAs in viral infections: RNA viruses use old dogs for new tricks. Non-coding RNA Research 2019, 4, 46 -53.

AMA Style

Stefan Stamm, J. Stephen Lodmell. C/D box snoRNAs in viral infections: RNA viruses use old dogs for new tricks. Non-coding RNA Research. 2019; 4 (2):46-53.

Chicago/Turabian Style

Stefan Stamm; J. Stephen Lodmell. 2019. "C/D box snoRNAs in viral infections: RNA viruses use old dogs for new tricks." Non-coding RNA Research 4, no. 2: 46-53.

Review
Published: 15 July 2016 in Viruses
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The Bunyaviridae represents the largest family of segmented RNA viruses, which infect a staggering diversity of plants, animals, and insects. Within the family Bunyaviridae, the Phlebovirus genus includes several important human and animal pathogens, including Rift Valley fever virus (RVFV), severe fever with thrombocytopenia syndrome virus (SFTSV), Uukuniemi virus (UUKV), and the sandfly fever viruses. The phleboviruses have small tripartite RNA genomes that encode a repertoire of 5–7 proteins. These few proteins accomplish the daunting task of recognizing and specifically packaging a tri-segment complement of viral genomic RNA in the midst of an abundance of host components. The critical nucleation events that eventually lead to virion production begin early on in the host cytoplasm as the first strands of nascent viral RNA (vRNA) are synthesized. The interaction between the vRNA and the viral nucleocapsid (N) protein effectively protects and masks the RNA from the host, and also forms the ribonucleoprotein (RNP) architecture that mediates downstream interactions and drives virion formation. Although the mechanism by which all three genomic counterparts are selectively co-packaged is not completely understood, we are beginning to understand the hierarchy of interactions that begins with N-RNA packaging and culminates in RNP packaging into new virus particles. In this review we focus on recent progress that highlights the molecular basis of RNA genome packaging in the phleboviruses.

ACS Style

Katherine E. Hornak; Jean-Marc Lanchy; J. Stephen Lodmell. RNA Encapsidation and Packaging in the Phleboviruses. Viruses 2016, 8, 194 .

AMA Style

Katherine E. Hornak, Jean-Marc Lanchy, J. Stephen Lodmell. RNA Encapsidation and Packaging in the Phleboviruses. Viruses. 2016; 8 (7):194.

Chicago/Turabian Style

Katherine E. Hornak; Jean-Marc Lanchy; J. Stephen Lodmell. 2016. "RNA Encapsidation and Packaging in the Phleboviruses." Viruses 8, no. 7: 194.

Journal article
Published: 22 June 2015 in Computational Biology and Chemistry
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Rift Valley fever virus (RVFV) is a potent human and livestock pathogen endemic to sub-Saharan Africa and the Arabian Peninsula that has potential to spread to other parts of the world. Although there is no proven effective and safe treatment for RVFV infections, a potential therapeutic target is the virally encoded nucleocapsid protein (N). During the course of infection, N binds to viral RNA, and perturbation of this interaction can inhibit viral replication. To gain insight into how N recognizes viral RNA specifically, we designed an algorithm that uses a distance matrix and multidimensional scaling to compare the predicted secondary structures of known N-binding RNAs, or aptamers, that were isolated and characterized in previous in vitro evolution experiment. These aptamers did not exhibit overt sequence or predicted structure similarity, so we employed bioinformatic methods to propose novel aptamers based on analysis and clustering of secondary structures. We screened and scored the predicted secondary structures of novel randomly generated RNA sequences in silico and selected several of these putative N-binding RNAs whose secondary structures were similar to those of known N-binding RNAs. We found that overall the in silico generated RNA sequences bound well to N in vitro. Furthermore, introduction of these RNAs into cells prior to infection with RVFV inhibited viral replication in cell culture. This proof of concept study demonstrates how the predictive power of bioinformatics and the empirical power of biochemistry can be jointly harnessed to discover, synthesize, and test new RNA sequences that bind tightly to RVFV N protein. The approach would be easily generalizable to other applications.

ACS Style

Mary Ellenbecker; Jeremy St. Goddard; Alec Sundet; Jean-Marc Lanchy; Douglas Raiford; J.Stephen Lodmell. Computational prediction and biochemical characterization of novel RNA aptamers to Rift Valley fever virus nucleocapsid protein. Computational Biology and Chemistry 2015, 58, 120 -125.

AMA Style

Mary Ellenbecker, Jeremy St. Goddard, Alec Sundet, Jean-Marc Lanchy, Douglas Raiford, J.Stephen Lodmell. Computational prediction and biochemical characterization of novel RNA aptamers to Rift Valley fever virus nucleocapsid protein. Computational Biology and Chemistry. 2015; 58 ():120-125.

Chicago/Turabian Style

Mary Ellenbecker; Jeremy St. Goddard; Alec Sundet; Jean-Marc Lanchy; Douglas Raiford; J.Stephen Lodmell. 2015. "Computational prediction and biochemical characterization of novel RNA aptamers to Rift Valley fever virus nucleocapsid protein." Computational Biology and Chemistry 58, no. : 120-125.

Research article
Published: 29 May 2012 in Journal of Biomolecular Screening
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Rift Valley fever virus (RVFV) is an emerging infectious pathogen that causes severe disease in humans and livestock and has the potential for global spread. Currently, there is no proven effective treatment for RVFV infection, and there is no licensed vaccine. Inhibition of RNA binding to the essential viral nucleocapsid (N) protein represents a potential antiviral therapeutic strategy because all of the functions performed by N during infection involve RNA binding. To target this interaction, we developed a fluorescence polarization–based high-throughput drug-screening assay and tested 26 424 chemical compounds for their ability to disrupt an N-RNA complex. From libraries of Food and Drug Administration–approved drugs, druglike molecules, and natural product extracts, we identified several lead compounds that are promising candidates for medicinal chemistry.

ACS Style

Mary Ellenbecker; Jean-Marc Lanchy; J. Stephen Lodmell. Identification of Rift Valley Fever Virus Nucleocapsid Protein-RNA Binding Inhibitors Using a High-Throughput Screening Assay. Journal of Biomolecular Screening 2012, 17, 1062 -1070.

AMA Style

Mary Ellenbecker, Jean-Marc Lanchy, J. Stephen Lodmell. Identification of Rift Valley Fever Virus Nucleocapsid Protein-RNA Binding Inhibitors Using a High-Throughput Screening Assay. Journal of Biomolecular Screening. 2012; 17 (8):1062-1070.

Chicago/Turabian Style

Mary Ellenbecker; Jean-Marc Lanchy; J. Stephen Lodmell. 2012. "Identification of Rift Valley Fever Virus Nucleocapsid Protein-RNA Binding Inhibitors Using a High-Throughput Screening Assay." Journal of Biomolecular Screening 17, no. 8: 1062-1070.

Journal article
Published: 31 March 2012 in Antiviral Research
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Nucleocapsid protein (N) is an essential RNA binding protein in many RNA viruses. During replication, N protein encapsidates viral genomic and antigenomic RNA, but not viral mRNA or other cellular RNAs. To discriminate between different species of RNA in a host cell, it is likely that N interacts with specific sequences and/or secondary structures on its target RNA. In this study, we explore the RNA binding properties of N using both natural and artificially selected RNAs as ligands. We found that N binds to RNAs that resemble the terminal panhandle structures of RVFV genomic and antigenomic RNA. Furthermore, we used SELEX to isolate RNA aptamers that bound N with high affinity and determined that N specifically recognizes and binds to GAUU and pyrimidine/guanine motifs. Interestingly, BLAST analysis revealed the presence of these motifs within the coding region of the viral genome, suggesting that N may interact with non-terminal viral RNA sequences during replication. Finally, the aptamer RNAs were used to construct a sensitive fluorescence based sensor of N binding with potential applications for drug screening and imaging methodologies.

ACS Style

Mary Ellenbecker; Leila Sears; Ping Li; Jean-Marc Lanchy; J. Stephen Lodmell. Characterization of RNA aptamers directed against the nucleocapsid protein of Rift Valley fever virus. Antiviral Research 2012, 93, 330 -339.

AMA Style

Mary Ellenbecker, Leila Sears, Ping Li, Jean-Marc Lanchy, J. Stephen Lodmell. Characterization of RNA aptamers directed against the nucleocapsid protein of Rift Valley fever virus. Antiviral Research. 2012; 93 (3):330-339.

Chicago/Turabian Style

Mary Ellenbecker; Leila Sears; Ping Li; Jean-Marc Lanchy; J. Stephen Lodmell. 2012. "Characterization of RNA aptamers directed against the nucleocapsid protein of Rift Valley fever virus." Antiviral Research 93, no. 3: 330-339.

Journal article
Published: 14 August 2009 in Journal of Molecular Biology
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Full-length unspliced genomic RNA plays critical roles in HIV replication, serving both as mRNA for the synthesis of the key viral polyproteins Gag and Gag-Pol and as genomic RNA for encapsidation into assembling viral particles. We show that a second gag mRNA species that differs from the genomic RNA molecule by the absence of an intron in the 5′ untranslated region (5′UTR) is produced during HIV-2 replication in cell culture and in infected patients. We developed a cotransfection system in which epitopically tagged Gag proteins can be traced back to their mRNA origins in the translation pool. We show that a disproportionate amount of Gag is translated from 5′UTR intron-spliced mRNAs, demonstrating a role for the 5′UTR intron in the regulation of gag translation. To further characterize the effects of the HIV-2 5′UTR on translation, we fused wild-type, spliced, or mutant leader RNA constructs to a luciferase reporter gene and assayed their translation in reticulocyte lysates. These assays confirmed that leaders lacking the 5′UTR intron increased translational efficiency compared to that of the unspliced leader. In addition, we found that removal or mutagenesis of the C-box, a pyrimidine-rich sequence located in the 5′UTR intron and previously shown to affect RNA dimerization, also strongly influenced translational efficiency. These results suggest that the splicing of both the 5′UTR intron and the C-box element have key roles in regulation of HIV-2 gag translation in vitro and in vivo.

ACS Style

Christy L. Strong; Jean-Marc Lanchy; Abdoulaye Dieng-Sarr; Phyllis J. Kanki; J. Stephen Lodmell. A 5′UTR-Spliced mRNA Isoform Is Specialized for Enhanced HIV-2 gag Translation. Journal of Molecular Biology 2009, 391, 426 -437.

AMA Style

Christy L. Strong, Jean-Marc Lanchy, Abdoulaye Dieng-Sarr, Phyllis J. Kanki, J. Stephen Lodmell. A 5′UTR-Spliced mRNA Isoform Is Specialized for Enhanced HIV-2 gag Translation. Journal of Molecular Biology. 2009; 391 (2):426-437.

Chicago/Turabian Style

Christy L. Strong; Jean-Marc Lanchy; Abdoulaye Dieng-Sarr; Phyllis J. Kanki; J. Stephen Lodmell. 2009. "A 5′UTR-Spliced mRNA Isoform Is Specialized for Enhanced HIV-2 gag Translation." Journal of Molecular Biology 391, no. 2: 426-437.

Journal article
Published: 15 January 2009 in Journal of Virology
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The packaging signal (ψ) of human immunodeficiency virus type 2 (HIV-2) is present in the 5′ noncoding region of RNA and contains a 10-nucleotide palindrome (pal; 5′-392-GGAGUGCUCC) located upstream of the dimerization signal stem-loop 1 (SL1). pal has been shown to be functionally important in vitro and in vivo. We previously showed that the 3′ side of pal (GCUCC-3′) is involved in base-pairing interactions with a sequence downstream of SL1 to make an extended SL1, which is important for replication in vivo and the regulation of dimerization in vitro. However, the role of the 5′ side of pal (5′-GGAGU) was less clear. Here, we characterized this role using an in vivo SELEX approach. We produced a population of HIV-2 DNA genomes with random sequences within the 5′ side of pal and transfected these into COS-7 cells. Viruses from COS-7 cells were used to infect C8166 permissive cells. After several weeks of serial passage in C8166 cells, surviving viruses were sequenced. On the 5′ side of pal there was a striking convergence toward a GGRGN consensus sequence. Individual clones with consensus and nonconsensus sequences were tested in infectivity and packaging assays. Analysis of individuals that diverged from the consensus sequence showed normal viral RNA and protein synthesis but had replication defects and impaired RNA packaging. These findings clearly indicate that the GGRG motif is essential for viral replication and genomic RNA packaging.

ACS Style

Tayyba T. Baig; Jean-Marc Lanchy; J. Stephen Lodmell. Randomization and In Vivo Selection Reveal a GGRG Motif Essential for Packaging Human Immunodeficiency Virus Type 2 RNA. Journal of Virology 2009, 83, 802 -810.

AMA Style

Tayyba T. Baig, Jean-Marc Lanchy, J. Stephen Lodmell. Randomization and In Vivo Selection Reveal a GGRG Motif Essential for Packaging Human Immunodeficiency Virus Type 2 RNA. Journal of Virology. 2009; 83 (2):802-810.

Chicago/Turabian Style

Tayyba T. Baig; Jean-Marc Lanchy; J. Stephen Lodmell. 2009. "Randomization and In Vivo Selection Reveal a GGRG Motif Essential for Packaging Human Immunodeficiency Virus Type 2 RNA." Journal of Virology 83, no. 2: 802-810.

Journal article
Published: 17 July 2008 in Retrovirology
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Genomic RNA dimerization is an important process in the formation of an infectious lentiviral particle. One of the signals involved is the stem-loop 1 (SL1) element located in the leader region of lentiviral genomic RNAs which also plays a role in encapsidation and reverse transcription. Recent studies revealed that HIV types 1 and 2 leader RNAs adopt different conformations that influence the presentation of RNA signals such as SL1. To determine whether common mechanisms of SL1 regulation exist among divergent lentiviral leader RNAs, here we compare the dimerization properties of SIVmac239, HIV-1, and HIV-2 leader RNA fragments using homologous constructs and experimental conditions. Prior studies from several groups have employed a variety of constructs and experimental conditions. Although some idiosyncratic differences in the dimerization details were observed, we find unifying principles in the regulation strategies of the three viral RNAs through long- and short-range base pairing interactions. Presentation and efficacy of dimerization through SL1 depends strongly upon the formation or dissolution of the lower stem of SL1 called stem B. SL1 usage may also be down-regulated by long-range interactions involving sequences between SL1 and the first codons of the gag gene. Despite their sequence differences, all three lentiviral RNAs tested in this study showed a local regulation of dimerization through the stabilization of SL1.

ACS Style

Tayyba T Baig; Christy L Strong; J Stephen Lodmell; Jean-Marc Lanchy. Regulation of primate lentiviral RNA dimerization by structural entrapment. Retrovirology 2008, 5, 1 -16.

AMA Style

Tayyba T Baig, Christy L Strong, J Stephen Lodmell, Jean-Marc Lanchy. Regulation of primate lentiviral RNA dimerization by structural entrapment. Retrovirology. 2008; 5 (1):1-16.

Chicago/Turabian Style

Tayyba T Baig; Christy L Strong; J Stephen Lodmell; Jean-Marc Lanchy. 2008. "Regulation of primate lentiviral RNA dimerization by structural entrapment." Retrovirology 5, no. 1: 1-16.

Journal article
Published: 01 April 2007 in Journal of Virology
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Genomic RNA encapsidation in lentiviruses is a highly selective and regulated process. The unspliced RNA molecules are selected for encapsidation from a pool of many different viral and cellular RNA species. Moreover, two molecules are encapsidated per viral particle, where they are found associated as a dimer. In this study, we demonstrate that a 10-nucleotide palindromic sequence (pal) located at the 3′ end of the ψ encapsidation signal is critical for human immunodeficiency virus type 2 (HIV-2) replication and affects genomic RNA encapsidation. We used short-term and long-term culture of pal-mutated viruses in permissive C8166 cells and their phenotypic reversion to show the existence of a structurally extended SL1 during HIV-2 replication, formed by the interaction of the 3′ end of the pal within ψ with a motif located downstream of SL1. The stem extending HIV-2 SL1 is structurally similar to stem B described for HIV-1 SL1. Despite the high degree of phylogenetic conservation, these results show that mutant viruses are viable when the autocomplementary nature of the pal sequence is disrupted, but not without a stable stem B. Our observations show that formation of the extended SL1 is necessary during viral replication and positively affects HIV-2 genomic RNA encapsidation. Sequestration of part of the packaging signal into SL1 may be a means of regulating its presentation during the replication cycle.

ACS Style

Jean-Marc Lanchy; J. Stephen Lodmell. An Extended Stem-Loop 1 Is Necessary for Human Immunodeficiency Virus Type 2 Replication and Affects Genomic RNA Encapsidation. Journal of Virology 2007, 81, 3285 -3292.

AMA Style

Jean-Marc Lanchy, J. Stephen Lodmell. An Extended Stem-Loop 1 Is Necessary for Human Immunodeficiency Virus Type 2 Replication and Affects Genomic RNA Encapsidation. Journal of Virology. 2007; 81 (7):3285-3292.

Chicago/Turabian Style

Jean-Marc Lanchy; J. Stephen Lodmell. 2007. "An Extended Stem-Loop 1 Is Necessary for Human Immunodeficiency Virus Type 2 Replication and Affects Genomic RNA Encapsidation." Journal of Virology 81, no. 7: 3285-3292.

Comparative study
Published: 30 April 2005 in Computational Biology and Chemistry
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The Ribosome Builder is a software project that provides tools and techniques to create dynamic models of macromolecular systems from the rapidly growing numbers of atomic structural models. It includes a computer program that allows the user to assemble the multiple molecular components within a 3D space and to define the hypothetical interactions of these components with the initial goal of understanding protein translation at an atomic level of detail. The program employs a simplified molecular dynamics forcefield that can simulate the long time-scale events, such as docking of translation factors and mRNA translocation. An embedded scripting language and Application Programming Interface (API) enable the creation of Steered Molecular Dynamics (SMD) simulations through the programmable application of external forces and torques on atoms and bonds. A graphical interface is provided for displaying and interacting with models, recording movies of molecular dynamics movements, and creating annotated 3D simulations of complex macromolecular events. Initial applications of the project include simulation of tetraloop folding, docking of an mRNA on the 30S subunit and a schematic simulation of the translation elongation cycle. The program is an open source project released under the GNU public license.

ACS Style

William Knight; Walter Hill; J. Stephen Lodmell. Ribosome Builder: A software project to simulate the ribosome. Computational Biology and Chemistry 2005, 29, 163 -174.

AMA Style

William Knight, Walter Hill, J. Stephen Lodmell. Ribosome Builder: A software project to simulate the ribosome. Computational Biology and Chemistry. 2005; 29 (2):163-174.

Chicago/Turabian Style

William Knight; Walter Hill; J. Stephen Lodmell. 2005. "Ribosome Builder: A software project to simulate the ribosome." Computational Biology and Chemistry 29, no. 2: 163-174.