BST-2 is rapidly down-regulated from the cell surface by the HIV-1 protein Vpu: Evidence for a post-ER mechanism of Vpu-action

Mark Skasko*, Andrey Tokarev, Cheng Chang Chen, Wolfgang B. Fischer, Satish K. Pillai, John Guatelli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Recent evidence suggests that transmembrane domain (TMD) interactions are essential for HIV-1 Vpu-mediated antagonism of the restriction factor BST-2/tetherin. We made Vpu TMD mutants to study the mechanism of BST-2 antagonism. Vpu-I17A, -A18F, -W22L, and -S23L co-localized with BST-2 within endosomal membranes while effectively enhancing virion release and down-regulating surface BST-2. However, Vpu-A18H was confined to an endoplasmic reticulum (ER)-like distribution, resulting in impaired down-regulation of BST-2 and reduced virion release. Brefeldin A confined wild type Vpu to the ER, resulting in a similarly impaired phenotype, as did the addition of a C-terminal ER-retention signal to Vpu. We determined the half-life of cell-surface BST-2 to be ~. 8. hours, whereas Vpu mediated an ~. 80% reduction of surface BST-2 within 6. hours, suggesting that TMD interactions between Vpu and BST-2 occur within post-ER membranes to directly and rapidly remove BST-2 from the cell surface and relieve restricted virion release.

Original languageEnglish
Pages (from-to)65-77
Number of pages13
JournalVirology
Volume411
Issue number1
DOIs
StatePublished - 1 Mar 2011

Keywords

  • Brefeldin A
  • BST-2
  • CD4
  • Endoplasmic reticulum
  • Tetherin
  • Vpu

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