Cargando…

Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses

Proteasomes are intracellular structures responsible for protein degradation. The 20S proteasome is a core catalytic element of the proteasome assembly. Variations of catalytic subunits generate different forms of 20S proteasomes including immunoproteasomes (iPs), which are present mostly in the imm...

Descripción completa

Detalles Bibliográficos
Autores principales: Vagapova, Elmira, Burov, Alexander, Spasskaya, Daria, Lebedev, Timofey, Astakhova, Tatiana, Spirin, Pavel, Prassolov, Vladimir, Karpov, Vadim, Morozov, Alexey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150886/
https://www.ncbi.nlm.nih.gov/pubmed/34066177
http://dx.doi.org/10.3390/cells10051185
_version_ 1783698253433274368
author Vagapova, Elmira
Burov, Alexander
Spasskaya, Daria
Lebedev, Timofey
Astakhova, Tatiana
Spirin, Pavel
Prassolov, Vladimir
Karpov, Vadim
Morozov, Alexey
author_facet Vagapova, Elmira
Burov, Alexander
Spasskaya, Daria
Lebedev, Timofey
Astakhova, Tatiana
Spirin, Pavel
Prassolov, Vladimir
Karpov, Vadim
Morozov, Alexey
author_sort Vagapova, Elmira
collection PubMed
description Proteasomes are intracellular structures responsible for protein degradation. The 20S proteasome is a core catalytic element of the proteasome assembly. Variations of catalytic subunits generate different forms of 20S proteasomes including immunoproteasomes (iPs), which are present mostly in the immune cells. Certain cells of the immune system are primary targets of retroviruses. It has been shown that several viral proteins directly affect proteasome functionality, while inhibition of proteasome activity with broad specificity proteasome inhibitors stimulates viral transduction. Here we specifically addressed the role of the immunoproteasomes during early stages of viral transduction and investigated the effects of specific immunoproteasome inhibition and activation prior to infection using a panel of cell lines. Inhibition of iPs in hematopoietic cells with immunoproteasome-specific inhibitor ONX-0914 resulted in increased infection by VSV-G pseudotyped lentiviruses. Moreover, a tendency for increased infection of cloned cells with endogenously decreased proteasome activity was revealed. Conversely, activation of iPs by IFN-γ markedly reduced the viral infectivity, which was rescued upon simultaneous immunoproteasome inhibition. Our results indicate that immunoproteasome activity might be determinative for the cellular antiretroviral resistance at least for the cells with high iP content. Finally, therapeutic application of immunoproteasome inhibitors might promote retroviral infection of cells in vivo.
format Online
Article
Text
id pubmed-8150886
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-81508862021-05-27 Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses Vagapova, Elmira Burov, Alexander Spasskaya, Daria Lebedev, Timofey Astakhova, Tatiana Spirin, Pavel Prassolov, Vladimir Karpov, Vadim Morozov, Alexey Cells Article Proteasomes are intracellular structures responsible for protein degradation. The 20S proteasome is a core catalytic element of the proteasome assembly. Variations of catalytic subunits generate different forms of 20S proteasomes including immunoproteasomes (iPs), which are present mostly in the immune cells. Certain cells of the immune system are primary targets of retroviruses. It has been shown that several viral proteins directly affect proteasome functionality, while inhibition of proteasome activity with broad specificity proteasome inhibitors stimulates viral transduction. Here we specifically addressed the role of the immunoproteasomes during early stages of viral transduction and investigated the effects of specific immunoproteasome inhibition and activation prior to infection using a panel of cell lines. Inhibition of iPs in hematopoietic cells with immunoproteasome-specific inhibitor ONX-0914 resulted in increased infection by VSV-G pseudotyped lentiviruses. Moreover, a tendency for increased infection of cloned cells with endogenously decreased proteasome activity was revealed. Conversely, activation of iPs by IFN-γ markedly reduced the viral infectivity, which was rescued upon simultaneous immunoproteasome inhibition. Our results indicate that immunoproteasome activity might be determinative for the cellular antiretroviral resistance at least for the cells with high iP content. Finally, therapeutic application of immunoproteasome inhibitors might promote retroviral infection of cells in vivo. MDPI 2021-05-12 /pmc/articles/PMC8150886/ /pubmed/34066177 http://dx.doi.org/10.3390/cells10051185 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vagapova, Elmira
Burov, Alexander
Spasskaya, Daria
Lebedev, Timofey
Astakhova, Tatiana
Spirin, Pavel
Prassolov, Vladimir
Karpov, Vadim
Morozov, Alexey
Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses
title Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses
title_full Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses
title_fullStr Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses
title_full_unstemmed Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses
title_short Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses
title_sort immunoproteasome activity and content determine hematopoietic cell sensitivity to onx-0914 and to the infection of cells with lentiviruses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150886/
https://www.ncbi.nlm.nih.gov/pubmed/34066177
http://dx.doi.org/10.3390/cells10051185
work_keys_str_mv AT vagapovaelmira immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT burovalexander immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT spasskayadaria immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT lebedevtimofey immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT astakhovatatiana immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT spirinpavel immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT prassolovvladimir immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT karpovvadim immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses
AT morozovalexey immunoproteasomeactivityandcontentdeterminehematopoieticcellsensitivitytoonx0914andtotheinfectionofcellswithlentiviruses