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Serine phosphorylation of HIV-1 Vpu and its binding to tetherin regulates interaction with clathrin adaptors

Kueck, Tonya; Foster, Toshana L.; Weinelt, Julia; Sumner, Jonathan C.; Pickering, Suzanne; Neil, Stuart J. D.


Tonya Kueck

Julia Weinelt

Jonathan C. Sumner

Suzanne Pickering

Stuart J. D. Neil


HIV-1 Vpu prevents incorporation of tetherin (BST2/ CD317) into budding virions and targets it for ESCRT-dependent endosomal degradation via a clathrin-dependent process. This requires a variant acidic dileucine-sorting motif (ExxxLV) in Vpu. Structural studies demonstrate that recombinant Vpu/tetherin fusions can form a ternary complex with the clathrin adaptor AP-1. However, open questions still exist about Vpu’s mechanism of action. Particularly, whether endosomal degradation and the recruitment of the E3 ubiquitin ligase SCFβTRCP1/2 to a conserved phosphorylated binding site, DSGNES, are required for antagonism. Re-evaluation of the phenotype of Vpu phosphorylation mutants and naturally occurring allelic variants reveals that the requirement for the Vpu phosphoserine motif in tetherin antagonism is dissociable from SCFβTRCP1/2 and ESCRT-dependent tetherin degradation. Vpu phospho-mutants phenocopy ExxxLV mutants, and can be rescued by direct clathrin interaction in the absence of SCFβTRCP1/2 recruitment. Moreover, we demonstrate physical interaction between Vpu and AP-1 or AP-2 in cells. This requires Vpu/tetherin transmembrane domain interactions as well as the ExxxLV motif. Importantly, it also requires the Vpu phosphoserine motif and adjacent acidic residues. Taken together these data explain the discordance between the role of SCFβTRCP1/2 and Vpu phosphorylation in tetherin antagonism, and indicate that phosphorylation of Vpu in Vpu/tetherin complexes regulates promiscuous recruitment of adaptors, implicating clathrin-dependent sorting as an essential first step in tetherin antagonism.


Kueck, T., Foster, T. L., Weinelt, J., Sumner, J. C., Pickering, S., & Neil, S. J. D. (2015). Serine phosphorylation of HIV-1 Vpu and its binding to tetherin regulates interaction with clathrin adaptors. PLoS Pathogens, 11(8),

Journal Article Type Article
Acceptance Date Aug 11, 2015
Online Publication Date Aug 28, 2015
Publication Date Aug 28, 2015
Deposit Date Mar 21, 2019
Publicly Available Date Mar 21, 2019
Journal PLOS Pathogens
Print ISSN 1553-7366
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 11
Issue 8
Article Number e1005141
Public URL
Publisher URL


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