Tetherin is an interferon-inducible host protein that not only prevents the release of membrane-enveloped virus particles but also triggers activation of NF-κB to elicit the production of proinflammatory cytokines that alert neighboring cells. In Cell Host & Microbe, Neil and colleagues reveal that Tyr6 in the Src-homology 2 motif YDYCRV, present in the cytoplasmic tail, becomes phosphorylated during viral budding and activates Syk-TRAF2,TRAF6-TAK1 signaling pathways. Although Tyr6 is not needed for blockade of virion release, phosphorylation of tetherin is triggered by retention of virions at the plasma membrane. Tetherin is linked to the actin cytoskeleton via the Rac-GAP protein RICH2, which promotes clustering of tetherin during viral budding. This proximity in turn leads to Src kinase–mediated phosphorylation of tetherin tyrosine to initiate the intracellular signaling cascade. Notably, this tetherin cytoplasmic tail is subject to intense evolutionary pressure as viruses attempt to evade tetherin-mediated restriction.

Cell Host Microbe 16, 291–303 (2014)