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  1. Article ; Online: Kaposi's sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs.

    Murphy, James C / Harrington, Elena M / Schumann, Sophie / Vasconcelos, Elton J R / Mottram, Timothy J / Harper, Katherine L / Aspden, Julie L / Whitehouse, Adrian

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 300

    Abstract: Historically, ribosomes were viewed as unchanged homogeneous macromolecular machines with no regulatory capacity for mRNA translation. An emerging concept is that heterogeneity of ribosomal composition exists, exerting a regulatory function or ... ...

    Abstract Historically, ribosomes were viewed as unchanged homogeneous macromolecular machines with no regulatory capacity for mRNA translation. An emerging concept is that heterogeneity of ribosomal composition exists, exerting a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct specialised ribosomes that actively regulate mRNA translation. Viruses lack their own translational machinery and impose high translational demands on the host during replication. We explore the possibility that KSHV manipulates ribosome biogenesis producing specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic replication. We demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and the KSHV ORF11 protein, with small ribosomal subunit precursor complexes during lytic replication. BUD23 depletion resulted in significantly reduced viral gene expression, culminating in dramatic reduction of infectious virion production. Ribosome profiling demonstrated BUD23 is essential for reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the downstream coding sequence. Results provide mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes facilitating efficient translation of viral mRNAs.
    MeSH term(s) Herpesvirus 8, Human/genetics ; Virus Replication/genetics ; Proteomics ; Ribosomes/genetics ; Gene Expression Regulation, Viral
    Language English
    Publishing date 2023-01-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-35914-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: m

    Manners, Oliver / Baquero-Perez, Belinda / Mottram, Timothy J / Yonchev, Ivaylo D / Trevelyan, Christopher J / Harper, Katherine L / Menezes, Sarah / Patterson, Molly R / Macdonald, Andrew / Wilson, Stuart A / Aspden, Julie L / Whitehouse, Adrian

    Viruses

    2023  Volume 15, Issue 6

    Abstract: The epitranscriptomic ... ...

    Abstract The epitranscriptomic modification
    MeSH term(s) Herpesvirus 8, Human/genetics ; Virus Latency/genetics ; Cell Line, Tumor ; Signal Transduction ; RNA, Messenger/genetics ; Virus Replication ; Gene Expression Regulation, Viral
    Chemical Substances RNA, Messenger
    Language English
    Publishing date 2023-06-16
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v15061381
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: M Segment-Based Minigenomes and Virus-Like Particle Assays as an Approach To Assess the Potential of Tick-Borne

    Rezelj, Veronica V / Mottram, Timothy J / Hughes, Joseph / Elliott, Richard M / Kohl, Alain / Brennan, Benjamin

    Journal of virology

    2019  Volume 93, Issue 6

    Abstract: Bunyaviruses have a tripartite negative-sense RNA genome. Due to the segmented nature of these viruses, if two closely related viruses coinfect the same host or vector cell, it is possible that RNA segments from either of the two parental viruses will be ...

    Abstract Bunyaviruses have a tripartite negative-sense RNA genome. Due to the segmented nature of these viruses, if two closely related viruses coinfect the same host or vector cell, it is possible that RNA segments from either of the two parental viruses will be incorporated into progeny virions to give reassortant viruses. Little is known about the ability of tick-borne phleboviruses to reassort. The present study describes the development of minigenome assays for the tick-borne viruses Uukuniemi phlebovirus (UUKV) and Heartland phlebovirus (HRTV). We used these minigenome assays in conjunction with the existing minigenome system of severe fever with thrombocytopenia syndrome (SFTS) phlebovirus (SFTSV) to assess the abilities of viral N and L proteins to recognize, transcribe, and replicate the M segment-based minigenome of a heterologous virus. The highest minigenome activity was detected with the M segment-based minigenomes of cognate viruses. However, our findings indicate that several combinations utilizing N and L proteins of heterologous viruses resulted in M segment minigenome activity. This suggests that the M segment untranslated regions (UTRs) are recognized as functional promoters of transcription and replication by the N and L proteins of related viruses. Further, virus-like particle assays demonstrated that HRTV glycoproteins can package UUKV and SFTSV S and L segment-based minigenomes. Taken together, these results suggest that coinfection with these viruses could lead to the generation of viable reassortant progeny. Thus, the tools developed in this study could aid in understanding the role of genome reassortment in the evolution of these emerging pathogens in an experimental setting.
    MeSH term(s) Animals ; Bunyaviridae Infections/virology ; Cell Line ; Genome, Viral/genetics ; Mesocricetus ; Phlebovirus/genetics ; Phylogeny ; Promoter Regions, Genetic/genetics ; Ticks/virology ; Viral Nonstructural Proteins/genetics
    Chemical Substances Viral Nonstructural Proteins
    Language English
    Publishing date 2019-03-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.02068-18
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 609: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Dysregulation of the miR-30c/DLL4 axis by circHIPK3 is essential for KSHV lytic replication.

    Harper, Katherine L / Mottram, Timothy J / Anene, Chinedu A / Foster, Becky / Patterson, Molly R / McDonnell, Euan / Macdonald, Andrew / Westhead, David / Whitehouse, Adrian

    EMBO reports

    2022  Volume 23, Issue 5, Page(s) e54117

    Abstract: Non-coding RNA (ncRNA) regulatory networks are emerging as critical regulators of gene expression. These intricate networks of ncRNA:ncRNA interactions modulate multiple cellular pathways and impact the development and progression of multiple diseases. ... ...

    Abstract Non-coding RNA (ncRNA) regulatory networks are emerging as critical regulators of gene expression. These intricate networks of ncRNA:ncRNA interactions modulate multiple cellular pathways and impact the development and progression of multiple diseases. Herpesviruses, including Kaposi's sarcoma-associated herpesvirus, are adept at utilising ncRNAs, encoding their own as well as dysregulating host ncRNAs to modulate virus gene expression and the host response to infection. Research has mainly focused on unidirectional ncRNA-mediated regulation of target protein-coding transcripts; however, we identify a novel host ncRNA regulatory network essential for KSHV lytic replication in B cells. KSHV-mediated upregulation of the host cell circRNA, circHIPK3, is a key component of this network, functioning as a competing endogenous RNA of miR-30c, leading to increased levels of the miR-30c target, DLL4. Dysregulation of this network highlights a novel mechanism of cell cycle control during KSHV lytic replication in B cells. Importantly, disruption at any point within this novel ncRNA regulatory network has a detrimental effect on KSHV lytic replication, highlighting the essential nature of this network and potential for therapeutic intervention.
    MeSH term(s) B-Lymphocytes ; Herpesvirus 8, Human/genetics ; MicroRNAs/genetics ; RNA, Circular/genetics ; Up-Regulation
    Chemical Substances MicroRNAs ; RNA, Circular
    Language English
    Publishing date 2022-03-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.15252/embr.202154117
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5433: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 41: Show issues

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  5. Article ; Online: Characterization of the Zika virus induced small RNA response in Aedes aegypti cells.

    Varjak, Margus / Donald, Claire L / Mottram, Timothy J / Sreenu, Vattipally B / Merits, Andres / Maringer, Kevin / Schnettler, Esther / Kohl, Alain

    PLoS neglected tropical diseases

    2017  Volume 11, Issue 10, Page(s) e0006010

    Abstract: RNA interference (RNAi) controls arbovirus infections in mosquitoes. Two different RNAi pathways are involved in antiviral responses: the PIWI-interacting RNA (piRNA) and exogenous short interfering RNA (exo-siRNA) pathways, which are characterized by ... ...

    Abstract RNA interference (RNAi) controls arbovirus infections in mosquitoes. Two different RNAi pathways are involved in antiviral responses: the PIWI-interacting RNA (piRNA) and exogenous short interfering RNA (exo-siRNA) pathways, which are characterized by the production of virus-derived small RNAs of 25-29 and 21 nucleotides, respectively. The exo-siRNA pathway is considered to be the key mosquito antiviral response mechanism. In Aedes aegypti-derived cells, Zika virus (ZIKV)-specific siRNAs were produced and loaded into the exo-siRNA pathway effector protein Argonaute 2 (Ago2); although the knockdown of Ago2 did not enhance virus replication. Enhanced ZIKV replication was observed in a Dcr2-knockout cell line suggesting that the exo-siRNA pathway is implicated in the antiviral response. Although ZIKV-specific piRNA-sized small RNAs were detected, these lacked the characteristic piRNA ping-pong signature motif and were bound to Ago3 but not Piwi5 or Piwi6. Silencing of PIWI proteins indicated that the knockdown of Ago3, Piwi5 or Piwi6 did not enhance ZIKV replication and only Piwi4 displayed antiviral activity. We also report that the expression of ZIKV capsid (C) protein amplified the replication of a reporter alphavirus; although, unlike yellow fever virus C protein, it does not inhibit the exo-siRNA pathway. Our findings elucidate ZIKV-mosquito RNAi interactions that are important for understanding its spread.
    MeSH term(s) Aedes/cytology ; Aedes/virology ; Alphavirus/genetics ; Animals ; Capsid Proteins/genetics ; Cell Line ; Host-Pathogen Interactions ; Insect Proteins/genetics ; Insect Proteins/metabolism ; RNA Interference ; RNA, Small Interfering ; Virus Replication ; Yellow fever virus/genetics ; Zika Virus/genetics ; Zika Virus/physiology ; Zika Virus Infection/transmission
    Chemical Substances Capsid Proteins ; Insect Proteins ; RNA, Small Interfering
    Language English
    Publishing date 2017-10-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2429704-5
    ISSN 1935-2735 ; 1935-2735
    ISSN (online) 1935-2735
    ISSN 1935-2735
    DOI 10.1371/journal.pntd.0006010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Mutational analysis of Rift Valley fever phlebovirus nucleocapsid protein indicates novel conserved, functional amino acids.

    Mottram, Timothy J / Li, Ping / Dietrich, Isabelle / Shi, Xiaohong / Brennan, Benjamin / Varjak, Margus / Kohl, Alain

    PLoS neglected tropical diseases

    2017  Volume 11, Issue 12, Page(s) e0006155

    Abstract: Rift Valley fever phlebovirus (RVFV; Phenuiviridae, Phlebovirus) is an important mosquito-borne pathogen of both humans and ruminants. The RVFV genome is composed of tripartite, single stranded, negative or ambisense RNAs. The small (S) segment encodes ... ...

    Abstract Rift Valley fever phlebovirus (RVFV; Phenuiviridae, Phlebovirus) is an important mosquito-borne pathogen of both humans and ruminants. The RVFV genome is composed of tripartite, single stranded, negative or ambisense RNAs. The small (S) segment encodes both the nucleocapsid protein (N) and the non-structural protein (NSs). The N protein is responsible for the formation of the viral ribonucleoprotein (RNP) complexes, which are essential in the virus life cycle and for the transcription and replication of the viral genome. There is currently limited knowledge surrounding the roles of the RVFV nucleocapsid protein in viral infection other than its key functions: N protein multimerisation, encapsidation of the RNA genome and interactions with the RNA-dependent RNA polymerase, L. By bioinformatic comparison of the N sequences of fourteen phleboviruses, mutational analysis, minigenome assays and packaging assays, we have further characterised the RVFV N protein. Amino acids P11 and F149 in RVFV N play an essential role in the function of RNPs and are neither associated with N protein multimerisation nor known nucleocapsid protein functions and may have additional roles in the virus life cycle. Amino acid Y30 exhibited increased minigenome activity despite reduced RNA binding capacity. Additionally, we have determined that the N-terminal arm of N protein is not involved in N-L interactions. Elucidating the fundamental processes that involve the nucleocapsid protein will add to our understanding of this important viral protein and may influence future studies in the development of novel antiviral strategies.
    MeSH term(s) Amino Acid Sequence ; Animals ; Cell Line ; Cricetinae ; DNA Mutational Analysis ; Genome, Viral/genetics ; Nucleocapsid Proteins/genetics ; Protein Multimerization/genetics ; Protein Multimerization/physiology ; RNA, Viral/genetics ; RNA-Binding Proteins/genetics ; Rift Valley Fever/virology ; Rift Valley fever virus/genetics ; Sequence Alignment ; Virus Replication
    Chemical Substances Nucleocapsid Proteins ; RNA, Viral ; RNA-Binding Proteins
    Language English
    Publishing date 2017-12-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2429704-5
    ISSN 1935-2735 ; 1935-2735
    ISSN (online) 1935-2735
    ISSN 1935-2735
    DOI 10.1371/journal.pntd.0006155
    Database MEDical Literature Analysis and Retrieval System OnLINE

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