Abstract
SummaryTetherin (BST2/CD317) restricts the release of enveloped viral particles from infected cells. Coupled to this virion retention, hominid tetherins induce proinflammatory gene expression via activating NF-κB. We investigated the events initiating this tetherin-induced signaling and show that physical retention of retroviral particles induces the phosphorylation of conserved tyrosine residues in the cytoplasmic tails of tetherin dimers. This phosphorylation induces the recruitment of spleen tyrosine kinase (Syk), which is required for downstream NF-κB activation, indicating that the tetherin cytoplasmic tail resembles the hemi-immunoreceptor tyrosine-based activation motifs (hemITAMs) found in C-type lectin pattern recognition receptors. Retroviral-induced tetherin signaling is coupled to the cortical actin cytoskeleton via the Rac-GAP-containing protein RICH2 (ARHGAP44), and a naturally occurring tetherin polymorphism with reduced RICH2 binding exhibits decreased phosphorylation and NF-κB activation. Thus, upon virion retention, this linkage to the actin cytoskeleton likely triggers tetherin phosphorylation and subsequent signal transduction to induce an antiviral state.
Highlights
Tetherin is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles from infected cells
We investigated the events initiating this tetherininduced signaling and show that physical retention of retroviral particles induces the phosphorylation of conserved tyrosine residues in the cytoplasmic tails of tetherin dimers
This phosphorylation induces the recruitment of spleen tyrosine kinase (Syk), which is required for downstream NF-kB activation, indicating that the tetherin cytoplasmic tail resembles the hemiimmunoreceptor tyrosine-based activation motifs found in C-type lectin pattern recognition receptors
Summary
Tetherin (bone marrow stromal cell antigen 2 [BST2] or CD317) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles from infected cells (reviewed in Neil, 2013). Parallel tetherin dimers partition into budding virions such that after membrane scission, the GPI anchors of tetherin are predominantly retained in the viral membrane (Perez-Caballero et al, 2009; Venkatesh and Bieniasz, 2013). There are several examples of virally encoded countermeasures that target tetherin. These include the accessory proteins Nef and Vpu of primate and human lentiviruses, respectively, which target the tetherin orthologs of their host species (Neil, 2013), and numerous lines of evidence indicate that this function is maintained and selected for throughout infection and upon cross-species transmission (Gotz et al, 2012; Pickering et al, 2014; Sauter et al, 2012; Serra-Moreno et al, 2011). It is likely that the adaptation of Vpu to target human tetherin was a key event in the spread of HIV-1 group M to become the predominant agent of the HIV/ AIDS pandemic (Sauter et al, 2009)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
