English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

The transmembrane domains (TMDs) of integral membrane proteins do not merely function as membrane anchors but play active roles in many important biological processes. The downregulation of the CD4 coreceptor by the Vpu protein of HIV-1 is a prime example of a process that is dependent on specific properties of TMDs. Here we report the identification of Trp22 in the Vpu TMD and Gly415 in the CD4 TMD as critical determinants of Vpu-induced targeting of CD4 to endoplasmic reticulum (ER)-associated degradation (ERAD). The two residues participate in different aspects of ERAD targeting. Vpu Trp22 is required to prevent assembly of Vpu into an inactive, oligomeric form and to promote CD4 polyubiquitination and subsequent recruitment of the VCP-UFD1L-NPL4 dislocase complex. In the presence of a Vpu Trp22 mutant, CD4 remains integrally associated with the ER membrane, suggesting that dislocation from the ER into the cytosol is impaired. CD4 Gly415, on the other hand, contributes to CD4-Vpu interactions. We also identify two residues, Val20 and Ser23, in the Vpu TMD that mediate retention of Vpu and, by extension, CD4 in the ER. These findings highlight the exploitation of several TMD-mediated mechanisms by HIV-1 Vpu in order to downregulate CD4 and thus promote viral pathogenesis.

Transmembrane Domain Determinants of CD4 Downregulation by HIV-1 Vpu