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.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.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1111/tra.1240
