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...

Descripción completa

Guardado en:
Detalles Bibliográficos
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:
Acceso en línea:https://doaj.org/article/05385fe8f4224a13931c53c96d9a993f
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:05385fe8f4224a13931c53c96d9a993f
record_format dspace
spelling oai:doaj.org-article:05385fe8f4224a13931c53c96d9a993f2021-11-11T06:03:59ZBinding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx1553-73661553-7374https://doaj.org/article/05385fe8f4224a13931c53c96d9a993f2021-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570500/?tool=EBIhttps://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. Author summary Human Immunodeficiency Virus (HIV) is still a major public health issue. The understanding of the molecular battle occurring during viral infection, between HIV components and cellular antiviral factors, the so-called restriction factors, is a key determinant for new treatment development. Namely, HIV auxiliary proteins are powerful to induce the downregulation of cellular restriction factors by hijacking the Ubiquitin/proteasome pathway, in order to facilitate the completion of a well-processed HIV replication cycle. For instance, HIV-2 Vpx eases reverse transcription in myeloid cells by counteracting the SAMDH1 restriction factor. More recently, we discovered the ability of Vpx to induce the degradation of the HUSH epigenetic repressor complex to favor in turn, the expression of the provirus. In this study, we uncovered the mechanisms by which Vpx antagonizes TASOR, the core subunit of the HUSH complex. We highlighted key differences between Vpx-induced TASOR and SAMHD1 degradation. These findings will help to propose strategies to study or to target either HUSH or SAMHD1, especially in myeloid cells where SAMHD1 restriction operates.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 (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. Author summary Human Immunodeficiency Virus (HIV) is still a major public health issue. The understanding of the molecular battle occurring during viral infection, between HIV components and cellular antiviral factors, the so-called restriction factors, is a key determinant for new treatment development. Namely, HIV auxiliary proteins are powerful to induce the downregulation of cellular restriction factors by hijacking the Ubiquitin/proteasome pathway, in order to facilitate the completion of a well-processed HIV replication cycle. For instance, HIV-2 Vpx eases reverse transcription in myeloid cells by counteracting the SAMDH1 restriction factor. More recently, we discovered the ability of Vpx to induce the degradation of the HUSH epigenetic repressor complex to favor in turn, the expression of the provirus. In this study, we uncovered the mechanisms by which Vpx antagonizes TASOR, the core subunit of the HUSH complex. We highlighted key differences between Vpx-induced TASOR and SAMHD1 degradation. These findings will help to propose strategies to study or to target either HUSH or SAMHD1, especially in myeloid cells where SAMHD1 restriction operates.
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/05385fe8f4224a13931c53c96d9a993f
work_keys_str_mv AT michaelmmartin bindingtodcaf1distinguishestasorandsamhd1degradationbyhiv2vpx
AT roymatkovic bindingtodcaf1distinguishestasorandsamhd1degradationbyhiv2vpx
AT paulinelarrous bindingtodcaf1distinguishestasorandsamhd1degradationbyhiv2vpx
AT marinamorel bindingtodcaf1distinguishestasorandsamhd1degradationbyhiv2vpx
AT angeliquelasserre bindingtodcaf1distinguishestasorandsamhd1degradationbyhiv2vpx
AT virginievauthier bindingtodcaf1distinguishestasorandsamhd1degradationbyhiv2vpx
AT florencemargottingoguet bindingtodcaf1distinguishestasorandsamhd1degradationbyhiv2vpx
_version_ 1718439463070203904