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Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion

Type-I interferons (IFN-I) are the innate immune system’s principal defense against viral infections. Human immunodeficiency virus-1 (HIV-1) has evolved several ways to suppress or evade the host’s innate immunity in order to survive and replicate to sustain infection. Suppression of IFN-I is one am...

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Autores principales: Jeremiah, Sundararaj Stanleyraj, Miyakawa, Kei, Matsunaga, Satoko, Nishi, Mayuko, Kudoh, Ayumi, Takaoka, Akinori, Sawasaki, Tatsuya, Ryo, Akihide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110901/
https://www.ncbi.nlm.nih.gov/pubmed/33986734
http://dx.doi.org/10.3389/fmicb.2021.643407
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author Jeremiah, Sundararaj Stanleyraj
Miyakawa, Kei
Matsunaga, Satoko
Nishi, Mayuko
Kudoh, Ayumi
Takaoka, Akinori
Sawasaki, Tatsuya
Ryo, Akihide
author_facet Jeremiah, Sundararaj Stanleyraj
Miyakawa, Kei
Matsunaga, Satoko
Nishi, Mayuko
Kudoh, Ayumi
Takaoka, Akinori
Sawasaki, Tatsuya
Ryo, Akihide
author_sort Jeremiah, Sundararaj Stanleyraj
collection PubMed
description Type-I interferons (IFN-I) are the innate immune system’s principal defense against viral infections. Human immunodeficiency virus-1 (HIV-1) has evolved several ways to suppress or evade the host’s innate immunity in order to survive and replicate to sustain infection. Suppression of IFN-I is one among the multiple escape strategies used by HIV-1 to prevent its clearance. HIV-1 protease which helps in viral maturation has also been observed to cleave host cellular protein kinases. In this study we performed a comprehensive screening of a human kinase library using AlphaScreen assay and identified that TANK binding kinase-1 (TBK1) was cleaved by HIV-1 protease (PR). We demonstrate that PR cleaved TBK1 fails to phosphorylate IFN regulatory factor 3 (IRF3), thereby reducing the IFN-I promoter activity and further reveal that the PR mediated suppression of IFN-I could be counteracted by protease inhibitors (PI) in vitro. We have also revealed that mutations of HIV-1 PR that confer drug resistance to PIs reduce the enzyme’s ability to cleave TBK1. The findings of this study unearth a direct link between HIV-1 PR activity and evasion of innate immunity by the virus, the possible physiological relevance of which warrants to be determined.
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spelling pubmed-81109012021-05-12 Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion Jeremiah, Sundararaj Stanleyraj Miyakawa, Kei Matsunaga, Satoko Nishi, Mayuko Kudoh, Ayumi Takaoka, Akinori Sawasaki, Tatsuya Ryo, Akihide Front Microbiol Microbiology Type-I interferons (IFN-I) are the innate immune system’s principal defense against viral infections. Human immunodeficiency virus-1 (HIV-1) has evolved several ways to suppress or evade the host’s innate immunity in order to survive and replicate to sustain infection. Suppression of IFN-I is one among the multiple escape strategies used by HIV-1 to prevent its clearance. HIV-1 protease which helps in viral maturation has also been observed to cleave host cellular protein kinases. In this study we performed a comprehensive screening of a human kinase library using AlphaScreen assay and identified that TANK binding kinase-1 (TBK1) was cleaved by HIV-1 protease (PR). We demonstrate that PR cleaved TBK1 fails to phosphorylate IFN regulatory factor 3 (IRF3), thereby reducing the IFN-I promoter activity and further reveal that the PR mediated suppression of IFN-I could be counteracted by protease inhibitors (PI) in vitro. We have also revealed that mutations of HIV-1 PR that confer drug resistance to PIs reduce the enzyme’s ability to cleave TBK1. The findings of this study unearth a direct link between HIV-1 PR activity and evasion of innate immunity by the virus, the possible physiological relevance of which warrants to be determined. Frontiers Media S.A. 2021-04-27 /pmc/articles/PMC8110901/ /pubmed/33986734 http://dx.doi.org/10.3389/fmicb.2021.643407 Text en Copyright © 2021 Jeremiah, Miyakawa, Matsunaga, Nishi, Kudoh, Takaoka, Sawasaki and Ryo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Jeremiah, Sundararaj Stanleyraj
Miyakawa, Kei
Matsunaga, Satoko
Nishi, Mayuko
Kudoh, Ayumi
Takaoka, Akinori
Sawasaki, Tatsuya
Ryo, Akihide
Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion
title Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion
title_full Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion
title_fullStr Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion
title_full_unstemmed Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion
title_short Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion
title_sort cleavage of tank-binding kinase 1 by hiv-1 protease triggers viral innate immune evasion
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110901/
https://www.ncbi.nlm.nih.gov/pubmed/33986734
http://dx.doi.org/10.3389/fmicb.2021.643407
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