Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also...

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Autores principales:	Michaël M Martin, Roy Matkovic, Pauline Larrous, Marina Morel, Angélique Lasserre, Virginie Vauthier, Florence Margottin-Goguet
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/efe4c87f1eb74c0b9b94564335855a8f
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spelling	oai:doaj.org-article:efe4c87f1eb74c0b9b94564335855a8f2021-12-02T19:59:58ZBinding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.1553-73661553-737410.1371/journal.ppat.1009609https://doaj.org/article/efe4c87f1eb74c0b9b94564335855a8f2021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009609https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells.Michaël M MartinRoy MatkovicPauline LarrousMarina MorelAngélique LasserreVirginie VauthierFlorence Margottin-GoguetPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 10, p e1009609 (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 Michaël M Martin Roy Matkovic Pauline Larrous Marina Morel Angélique Lasserre Virginie Vauthier Florence Margottin-Goguet Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.
description	Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells.
format	article
author	Michaël M Martin Roy Matkovic Pauline Larrous Marina Morel Angélique Lasserre Virginie Vauthier Florence Margottin-Goguet
author_facet	Michaël M Martin Roy Matkovic Pauline Larrous Marina Morel Angélique Lasserre Virginie Vauthier Florence Margottin-Goguet
author_sort	Michaël M Martin
title	Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.
title_short	Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.
title_full	Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.
title_fullStr	Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.
title_full_unstemmed	Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.
title_sort	binding to dcaf1 distinguishes tasor and samhd1 degradation by hiv-2 vpx.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/efe4c87f1eb74c0b9b94564335855a8f
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Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.

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