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The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin.

Title: The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin.
Authors: Pardieu, C
Vigan, R
Wilson, SJ
Calvi, A
Zang, T
Bieniasz, P
Kellam, P
Towers, GJ
Neil, SJD
Item Type: Journal Article
Abstract: Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition.
Issue Date: 15-Apr-2010
Date of Acceptance: 3-Mar-2010
URI: http://hdl.handle.net/10044/1/61375
DOI: https://dx.doi.org/10.1371/journal.ppat.1000843
ISSN: 1553-7366
Publisher: Public Library of Science (PLoS)
Start Page: e1000843
End Page: e1000843
Journal / Book Title: PLoS Pathogens
Volume: 6
Issue: 4
Copyright Statement: © 2010 Pardieu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Antigens, CD
Cell Separation
Endosomes
Flow Cytometry
GPI-Linked Proteins
HIV Infections
HIV-1
HeLa Cells
Herpesviridae Infections
Herpesvirus 8, Human
Human Immunodeficiency Virus Proteins
Humans
Immediate-Early Proteins
Membrane Glycoproteins
Microscopy, Confocal
Reverse Transcriptase Polymerase Chain Reaction
Ubiquitin
Ubiquitination
Viral Regulatory and Accessory Proteins
Virion
Virus Release
Hela Cells
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Virology
Publication Status: Published
Conference Place: United States
Article Number: e1000843
Appears in Collections:Department of Medicine
Faculty of Medicine



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