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  1. Article ; Online: Chaperonin TRiC/CCT Participates in Mammarenavirus Multiplication in Human Cells via Interaction with the Viral Nucleoprotein.

    Sakabe, Saori / Witwit, Haydar / Khafaji, Roaa / Cubitt, Beatrice / de la Torre, Juan C

    Journal of virology

    2023  Volume 97, Issue 2, Page(s) e0168822

    Abstract: The eukaryotic chaperonin containing tailless complex polypeptide 1 ring complex (CCT, also known as TCP-1 Ring Complex, TRiC/CCT) participates in the folding of 5% to 10% of the cellular proteome and has been involved in the life cycle of several ... ...

    Abstract The eukaryotic chaperonin containing tailless complex polypeptide 1 ring complex (CCT, also known as TCP-1 Ring Complex, TRiC/CCT) participates in the folding of 5% to 10% of the cellular proteome and has been involved in the life cycle of several viruses, including dengue, Zika, and influenza viruses, but the mechanisms by which the TRiC/CCT complex contributes to virus multiplication remain poorly understood. Here, we document that the nucleoprotein (NP) of the mammarenavirus lymphocytic choriomeningitis virus (LCMV) is a substrate of the human TRiC/CCT complex, and that pharmacological inhibition of TRiC/CCT complex function, or RNAi-mediated knockdown of TRiC/CCT complex subunits, inhibited LCMV multiplication in human cells. We obtained evidence that the TRiC/CCT complex is required for the production of NP-containing virus-like particles (VLPs), and the activity of the virus ribonucleoprotein (vRNP) responsible for directing replication and transcription of the viral genome. Pharmacological inhibition of the TRIC/CCT complex also restricted multiplication of the live-attenuated vaccine candidates Candid#1 and ML29 of the hemorrhagic fever causing Junin (JUNV) and Lassa (LASV) mammarenaviruses, respectively. Our findings indicate that the TRiC/CCT complex is required for mammarenavirus multiplication and is an attractive candidate for the development of host directed antivirals against human-pathogenic mammarenaviruses.
    MeSH term(s) Humans ; Antiviral Agents ; Chaperonin Containing TCP-1/metabolism ; Lymphocytic choriomeningitis virus ; Nucleoproteins ; Virus Replication
    Chemical Substances Antiviral Agents ; Chaperonin Containing TCP-1 (EC 3.6.1.-) ; Nucleoproteins
    Language English
    Publishing date 2023-01-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.01688-22
    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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  2. Article ; Online: Activation of protein kinase receptor (PKR) plays a pro-viral role in mammarenavirus-infected cells.

    Witwit, Haydar / Khafaji, Roaa / Salaniwal, Arul / Kim, Arthur S / Cubitt, Beatrice / Jackson, Nathaniel / Ye, Chengjin / Weiss, Susan R / Martinez-Sobrido, Luis / de la Torre, Juan Carlos

    Journal of virology

    2024  Volume 98, Issue 3, Page(s) e0188323

    Abstract: Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double-stranded RNA (dsRNA) sensor protein kinase ... ...

    Abstract Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double-stranded RNA (dsRNA) sensor protein kinase receptor (PKR) pathway plays a critical role in the cell anti-viral response. Whether PKR can restrict the multiplication of the Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) and the mechanisms by which LCMV may counteract the anti-viral functions of PKR have not yet been investigated. Here we present evidence that LCMV infection results in very limited levels of PKR activation, but LCMV multiplication is enhanced in the absence of PKR. In contrast, infection with a recombinant LCMV with a mutation affecting the 3'-5' exonuclease (ExoN) activity of the viral nucleoprotein resulted in robust PKR activation in the absence of detectable levels of dsRNA, which was associated with severely restricted virus multiplication that was alleviated in the absence of PKR. However, pharmacological inhibition of PKR activation resulted in reduced levels of LCMV multiplication. These findings uncovered a complex role of the PKR pathway in LCMV-infected cells involving both pro- and anti-viral activities.IMPORTANCEAs with many other viruses, the prototypic Old World mammarenavirus LCMV can interfere with the host cell innate immune response to infection, which includes the dsRNA sensor PKR pathway. A detailed understanding of LCMV-PKR interactions can provide novel insights about mammarenavirus-host cell interactions and facilitate the development of effective anti-viral strategies against human pathogenic mammarenaviruses. In the present work, we present evidence that LCMV multiplication is enhanced in PKR-deficient cells, but pharmacological inhibition of PKR activation unexpectedly resulted in severely restricted propagation of LCMV. Likewise, we document a robust PKR activation in LCMV-infected cells in the absence of detectable levels of dsRNA. Our findings have revealed a complex role of the PKR pathway during LCMV infection and uncovered the activation of PKR as a druggable target for the development of anti-viral drugs against human pathogenic mammarenaviruses.
    MeSH term(s) Humans ; Arenaviridae/metabolism ; Cell Line ; Protein Kinases/metabolism ; Host-Pathogen Interactions ; Lymphocytic choriomeningitis virus/metabolism ; Carrier Proteins ; Lymphocytic Choriomeningitis ; Antiviral Agents ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
    Chemical Substances Protein Kinases (EC 2.7.-) ; Carrier Proteins ; Antiviral Agents ; eIF-2 Kinase (EC 2.7.11.1)
    Language English
    Publishing date 2024-02-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.01883-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

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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)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article: Activation of Protein Kinase R (PKR) Plays a Pro-Viral Role in Mammarenavirus Infected Cells.

    Witwit, Haydar / Khafaji, Roaa / Salaniwal, Arul / Kim, Arthur S / Cubitt, Beatrice / Jackson, Nathaniel / Ye, Chengjin / Weiss, Susan R / Martinez-Sobrido, Luis / de la Torre, Juan Carlos

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double strand (ds)RNA sensor protein kinase receptor ( ... ...

    Abstract Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double strand (ds)RNA sensor protein kinase receptor (PKR) pathway plays a critical role in the cell antiviral response. Whether PKR can restrict the multiplication of the Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) and the mechanisms by which LCMV may counteract the antiviral functions of PKR have not yet been investigated. Here we present evidence that LCMV infection results in very limited levels of PKR activation, but LCMV multiplication is enhanced in the absence of PKR. In contrast, infection with a recombinant LCMV with a mutation affecting the 3'-5' exonuclease (ExoN) activity of the viral nucleoprotein (NP) resulted in robust PKR activation in the absence of detectable levels of dsRNA, which was associated with severely restricted virus multiplication that was alleviated in the absence of PKR. However, pharmacological inhibition of PKR activation resulted in reduced levels of LCMV multiplication. These findings uncovered a complex role of the PKR pathway in LCMV-infected cells involving both pro-and antiviral activities.
    Language English
    Publishing date 2023-12-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.05.570143
    Database MEDical Literature Analysis and Retrieval System OnLINE

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