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A Genetic Screen Identifies a Critical Role for the WDR81-WDR91 Complex in the Trafficking and Degradation of Tetherin.


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Authors

Rapiteanu, Radu 
Davis, Luther J 
Williamson, James C 
Timms, Richard T 
Paul Luzio, J 

Abstract

Tetherin (BST2/CD317) is a viral restriction factor that anchors enveloped viruses to host cells and limits viral spread. The HIV-1 Vpu accessory protein counteracts tetherin by decreasing its cell surface expression and targeting it for ubiquitin-dependent endolysosomal degradation. Although the Vpu-mediated downregulation of tetherin has been extensively studied, the molecular details are not completely elucidated. We therefore used a forward genetic screen in human haploid KBM7 cells to identify novel genes required for tetherin trafficking. Our screen identified WDR81 as a novel gene required for tetherin trafficking and degradation in both the presence and absence of Vpu. WDR81 is a BEACH-domain containing protein that is also required for the degradation of EGF-stimulated epidermal growth factor receptor (EGFR) and functions in a complex with the WDR91 protein. In the absence of WDR81 the endolysosomal compartment appears swollen, with enlarged early and late endosomes and reduced delivery of endocytosed dextran to cathepsin-active lysosomes. Our data suggest a role for the WDR81-WDR91 complex in the fusion of endolysosomal compartments and the absence of WDR81 leads to impaired receptor trafficking and degradation.

Description

Keywords

CAMRQ2, EGFR, HIV-Vpu, KBM7, WDR81, WDR91, early endosomes, endocytosis, human haploid cells, lysosomes, tetherin, Antigens, CD, Carrier Proteins, Cell Membrane, Endosomes, GPI-Linked Proteins, HIV-1, HeLa Cells, Human Immunodeficiency Virus Proteins, Humans, Lysosomes, Nerve Tissue Proteins, Protein Transport, Viral Regulatory and Accessory Proteins

Journal Title

Traffic

Conference Name

Journal ISSN

1398-9219
1600-0854

Volume Title

17

Publisher

Wiley
Sponsorship
Medical Research Council (MR/M010007/1)
Wellcome Trust (101835/Z/13/Z)
Wellcome Trust (084957/Z/08/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (079895/Z/06/Z)
This work was supported by the Wellcome Trust, through a Principal Research Fellowship to PJL (084957/Z/08/Z) and Ph.D studentship to RR (079895/Z/06/Z), by MRC research grant MR/M010007/1 to JPL and by a BBSRC industrial CASE studentship with GSK Research and Development Ltd to LJD. The CIMR is in receipt of a Wellcome Trust strategic award 100140.