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

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

  • Traffic. 2016 Aug;17(8):940-58. doi: 10.1111/tra.12409.
Radu Rapiteanu 1,  Luther J Davis 2,  James C Williamson 1,  Richard T Timms 1,  J Paul Luzio 2,  Paul J Lehner 1
Affiliations

Affiliations

  • 1 Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building Biomedical Campus, Cambridge, CB2 0XY, UK.
  • 2 Departments of Medicine and Clinical Biochemistry, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building Biomedical Campus, Cambridge, CB2 0XY, UK.
PMID: 27126989 DOI: 10.1111/tra.12409
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.

Keywords

CAMRQ2; EGFR; HIV-Vpu; KBM7; WDR81; WDR91; early endosomes; endocytosis; human haploid cells; lysosomes; tetherin.

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