Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.

Viruses have evolved means to manipulate the host's ubiquitin-proteasome system, in order to down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases in...

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Autores principales:	Sofia Banchenko, Ferdinand Krupp, Christine Gotthold, Jörg Bürger, Andrea Graziadei, Francis J O'Reilly, Ludwig Sinn, Olga Ruda, Juri Rappsilber, Christian M T Spahn, Thorsten Mielke, Ian A Taylor, David Schwefel
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b63e6e33cdeb4efb8f380f91c2f56491
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spelling	oai:doaj.org-article:b63e6e33cdeb4efb8f380f91c2f564912021-12-02T20:00:26ZStructural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.1553-73661553-737410.1371/journal.ppat.1009775https://doaj.org/article/b63e6e33cdeb4efb8f380f91c2f564912021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009775https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Viruses have evolved means to manipulate the host's ubiquitin-proteasome system, in order to down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases involved in DNA replication, DNA repair and cell cycle regulation. CRL4DCAF1 specificity modulation by Vpx and Vpr from certain simian immunodeficiency viruses (SIV) leads to recruitment, poly-ubiquitylation and subsequent proteasomal degradation of the host restriction factor SAMHD1, resulting in enhanced virus replication in differentiated cells. To unravel the mechanism of SIV Vpr-induced SAMHD1 ubiquitylation, we conducted integrative biochemical and structural analyses of the Vpr protein from SIVs infecting Cercopithecus cephus (SIVmus). X-ray crystallography reveals commonalities between SIVmus Vpr and other members of the Vpx/Vpr family with regard to DCAF1 interaction, while cryo-electron microscopy and cross-linking mass spectrometry highlight a divergent molecular mechanism of SAMHD1 recruitment. In addition, these studies demonstrate how SIVmus Vpr exploits the dynamic architecture of the multi-subunit CRL4DCAF1 assembly to optimise SAMHD1 ubiquitylation. Together, the present work provides detailed molecular insight into variability and species-specificity of the evolutionary arms race between host SAMHD1 restriction and lentiviral counteraction through Vpx/Vpr proteins.Sofia BanchenkoFerdinand KruppChristine GottholdJörg BürgerAndrea GraziadeiFrancis J O'ReillyLudwig SinnOlga RudaJuri RappsilberChristian M T SpahnThorsten MielkeIan A TaylorDavid SchwefelPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 8, p e1009775 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Sofia Banchenko Ferdinand Krupp Christine Gotthold Jörg Bürger Andrea Graziadei Francis J O'Reilly Ludwig Sinn Olga Ruda Juri Rappsilber Christian M T Spahn Thorsten Mielke Ian A Taylor David Schwefel Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.
description	Viruses have evolved means to manipulate the host's ubiquitin-proteasome system, in order to down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases involved in DNA replication, DNA repair and cell cycle regulation. CRL4DCAF1 specificity modulation by Vpx and Vpr from certain simian immunodeficiency viruses (SIV) leads to recruitment, poly-ubiquitylation and subsequent proteasomal degradation of the host restriction factor SAMHD1, resulting in enhanced virus replication in differentiated cells. To unravel the mechanism of SIV Vpr-induced SAMHD1 ubiquitylation, we conducted integrative biochemical and structural analyses of the Vpr protein from SIVs infecting Cercopithecus cephus (SIVmus). X-ray crystallography reveals commonalities between SIVmus Vpr and other members of the Vpx/Vpr family with regard to DCAF1 interaction, while cryo-electron microscopy and cross-linking mass spectrometry highlight a divergent molecular mechanism of SAMHD1 recruitment. In addition, these studies demonstrate how SIVmus Vpr exploits the dynamic architecture of the multi-subunit CRL4DCAF1 assembly to optimise SAMHD1 ubiquitylation. Together, the present work provides detailed molecular insight into variability and species-specificity of the evolutionary arms race between host SAMHD1 restriction and lentiviral counteraction through Vpx/Vpr proteins.
format	article
author	Sofia Banchenko Ferdinand Krupp Christine Gotthold Jörg Bürger Andrea Graziadei Francis J O'Reilly Ludwig Sinn Olga Ruda Juri Rappsilber Christian M T Spahn Thorsten Mielke Ian A Taylor David Schwefel
author_facet	Sofia Banchenko Ferdinand Krupp Christine Gotthold Jörg Bürger Andrea Graziadei Francis J O'Reilly Ludwig Sinn Olga Ruda Juri Rappsilber Christian M T Spahn Thorsten Mielke Ian A Taylor David Schwefel
author_sort	Sofia Banchenko
title	Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.
title_short	Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.
title_full	Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.
title_fullStr	Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.
title_full_unstemmed	Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.
title_sort	structural insights into cullin4-ring ubiquitin ligase remodelling by vpr from simian immunodeficiency viruses.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/b63e6e33cdeb4efb8f380f91c2f56491
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Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.

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