title: The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation.
abstract: The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery, a highly conserved set of four hetero-oligomeric protein complexes, is required for multivesicular body formation, sorting ubiquitinylated membrane proteins for lysosomal degradation, cytokinesis and the final stages of assembly of a number of enveloped viruses, including the human immunodeficiency viruses. Here, we show an additional role for the ESCRT machinery in HIV-1 release. BST-2/tetherin is a restriction factor that impedes HIV release by tethering mature virus particles to the plasma membrane. We found that HRS, a key component of the ESCRT-0 complex, promotes efficient release of HIV-1 and that siRNA-mediated HRS depletion induces a BST-2/tetherin phenotype. This activity is related to the ability of the HIV-1 Vpu protein to down-regulate BST-2/tetherin. We found that BST-2/tetherin undergoes constitutive ESCRT-dependent sorting for lysosomal degradation and that this degradation is enhanced by Vpu expression. We demonstrate that Vpu-mediated BST-2/tetherin down-modulation and degradation require HRS (ESCRT-0) function and that knock down of HRS increases cellular levels of BST-2/tetherin and restricts virus release. Furthermore, HRS co-precipitates with Vpu and BST-2. Our results provide further insight into the mechanism by which Vpu counteracts BST-2/tetherin and promotes HIV-1 dissemination, and they highlight an additional role for the ESCRT machinery in virus release.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France. katy.janvier@inserm.fr
authors.forename: Katy
authors.initials: K
authors.lastname: Janvier
authors.forename: Annegret
authors.initials: A
authors.lastname: Pelchen-Matthews
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Renaud
authors.forename: Marina
authors.initials: M
authors.lastname: Caillet
authors.forename: Mark
authors.initials: M
authors.lastname: Marsh
authors.forename: Clarisse
authors.initials: C
authors.lastname: Berlioz-Torrent
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D014162:Transfection; D019562:Viral Load / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism / Q000502:physiology*; D014771:Virion / Q000187:drug effects; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D056827:Endosomal Sorting Complexes Required for Transport; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins