HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection

ABSTRACT Viral accessory proteins hijack host cell E3 ubiquitin ligases to antagonize innate/intrinsic defenses and thereby provide a more permissive environment for virus replication. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr reprograms CRL4DCAF1 E3 to antagonize select post...

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Autores principales:	Junpeng Yan, Ming-Chieh Shun, Caili Hao, Yi Zhang, Juan Qian, Kasia Hrecka, Maria DeLucia, Christina Monnie, Jinwoo Ahn, Jacek Skowronski
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	DNA repair human immunodeficiency virus innate immunity protein degradation ubiquitination Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/56ce2447f8324b7eadd44ac5a495e2e4
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spelling	oai:doaj.org-article:56ce2447f8324b7eadd44ac5a495e2e42021-11-15T15:58:21ZHIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection10.1128/mBio.01732-182150-7511https://doaj.org/article/56ce2447f8324b7eadd44ac5a495e2e42018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01732-18https://doaj.org/toc/2150-7511ABSTRACT Viral accessory proteins hijack host cell E3 ubiquitin ligases to antagonize innate/intrinsic defenses and thereby provide a more permissive environment for virus replication. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr reprograms CRL4DCAF1 E3 to antagonize select postreplication DNA repair enzymes, but the significance and role of these Vpr interactions are poorly understood. To gain additional insights, we performed a focused screen for substrates of CRL4DCAF1 E3 reprogrammed by HIV-1 Vpr among known postreplication DNA repair proteins and identified exonuclease 1 (Exo1) as a novel direct HIV-1 Vpr target. We show that HIV-1 Vpr recruits Exo1 to the CRL4DCAF1 E3 complex for ubiquitination and subsequent proteasome-dependent degradation and that Exo1 levels are depleted in HIV-1-infected cells in a Vpr-dependent manner. We also show that Exo1 inhibits HIV-1 replication in T cells. Notably, the antagonism of Exo1 is a conserved function of main group HIV-1 and its ancestor Vpr proteins in the simian immunodeficiency virus from chimpanzee (SIVcpz) lineage, further underscoring the relevance of our findings. Overall, our studies (i) reveal that HIV-1 Vpr extensively remodels the cellular postreplication DNA repair machinery by impinging on multiple repair pathways, (ii) support a model in which Vpr promotes HIV-1 replication by antagonizing select DNA repair enzymes, and (iii) highlight the importance of a new class of restrictions placed on HIV-1 replication in T cells by the cellular DNA repair machinery. IMPORTANCE HIV-1 polymerase reverse transcribes the viral RNA genome into imperfectly double-stranded proviral DNA, containing gaps and flaps, for integration into the host cell chromosome. HIV-1 reverse transcripts share characteristics with cellular DNA replication intermediates and are thought to be converted into fully double-stranded DNA by cellular postreplication DNA repair enzymes. Therefore, the finding that the HIV-1 accessory protein Vpr antagonizes select postreplication DNA repair enzymes that can process HIV-1 reverse transcripts has been surprising. Here, we show that one such Vpr-antagonized enzyme, exonuclease 1, inhibits HIV-1 replication in T cells. We identify exonuclease 1 as a member of a new class of HIV-1 restriction factors in T cells and propose that certain modes of DNA “repair” inhibit HIV-1 infection.Junpeng YanMing-Chieh ShunCaili HaoYi ZhangJuan QianKasia HreckaMaria DeLuciaChristina MonnieJinwoo AhnJacek SkowronskiAmerican Society for MicrobiologyarticleDNA repairhuman immunodeficiency virusinnate immunityprotein degradationubiquitinationMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA repair human immunodeficiency virus innate immunity protein degradation ubiquitination Microbiology QR1-502
spellingShingle	DNA repair human immunodeficiency virus innate immunity protein degradation ubiquitination Microbiology QR1-502 Junpeng Yan Ming-Chieh Shun Caili Hao Yi Zhang Juan Qian Kasia Hrecka Maria DeLucia Christina Monnie Jinwoo Ahn Jacek Skowronski HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection
description	ABSTRACT Viral accessory proteins hijack host cell E3 ubiquitin ligases to antagonize innate/intrinsic defenses and thereby provide a more permissive environment for virus replication. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr reprograms CRL4DCAF1 E3 to antagonize select postreplication DNA repair enzymes, but the significance and role of these Vpr interactions are poorly understood. To gain additional insights, we performed a focused screen for substrates of CRL4DCAF1 E3 reprogrammed by HIV-1 Vpr among known postreplication DNA repair proteins and identified exonuclease 1 (Exo1) as a novel direct HIV-1 Vpr target. We show that HIV-1 Vpr recruits Exo1 to the CRL4DCAF1 E3 complex for ubiquitination and subsequent proteasome-dependent degradation and that Exo1 levels are depleted in HIV-1-infected cells in a Vpr-dependent manner. We also show that Exo1 inhibits HIV-1 replication in T cells. Notably, the antagonism of Exo1 is a conserved function of main group HIV-1 and its ancestor Vpr proteins in the simian immunodeficiency virus from chimpanzee (SIVcpz) lineage, further underscoring the relevance of our findings. Overall, our studies (i) reveal that HIV-1 Vpr extensively remodels the cellular postreplication DNA repair machinery by impinging on multiple repair pathways, (ii) support a model in which Vpr promotes HIV-1 replication by antagonizing select DNA repair enzymes, and (iii) highlight the importance of a new class of restrictions placed on HIV-1 replication in T cells by the cellular DNA repair machinery. IMPORTANCE HIV-1 polymerase reverse transcribes the viral RNA genome into imperfectly double-stranded proviral DNA, containing gaps and flaps, for integration into the host cell chromosome. HIV-1 reverse transcripts share characteristics with cellular DNA replication intermediates and are thought to be converted into fully double-stranded DNA by cellular postreplication DNA repair enzymes. Therefore, the finding that the HIV-1 accessory protein Vpr antagonizes select postreplication DNA repair enzymes that can process HIV-1 reverse transcripts has been surprising. Here, we show that one such Vpr-antagonized enzyme, exonuclease 1, inhibits HIV-1 replication in T cells. We identify exonuclease 1 as a member of a new class of HIV-1 restriction factors in T cells and propose that certain modes of DNA “repair” inhibit HIV-1 infection.
format	article
author	Junpeng Yan Ming-Chieh Shun Caili Hao Yi Zhang Juan Qian Kasia Hrecka Maria DeLucia Christina Monnie Jinwoo Ahn Jacek Skowronski
author_facet	Junpeng Yan Ming-Chieh Shun Caili Hao Yi Zhang Juan Qian Kasia Hrecka Maria DeLucia Christina Monnie Jinwoo Ahn Jacek Skowronski
author_sort	Junpeng Yan
title	HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection
title_short	HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection
title_full	HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection
title_fullStr	HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection
title_full_unstemmed	HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection
title_sort	hiv-1 vpr reprograms clr4<sup>dcaf1</sup> e3 ubiquitin ligase to antagonize exonuclease 1-mediated restriction of hiv-1 infection
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/56ce2447f8324b7eadd44ac5a495e2e4
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HIV-1 Vpr Reprograms CLR4<sup>DCAF1</sup> E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection

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