Tetherin/BST2, a physiologically and therapeutically relevant regulator of platelet receptor signalling

The reactivity of platelets, which play a key role in the pathogenesis of atherothrombosis, is tightly regulated. The integral membrane protein tetherin/bone marrow stromal antigen-2 (BST-2) regulates membrane organization, altering both lipid and protein distribution within the plasma membrane. Because membrane microdomains have an established role in platelet receptor biology, we sought to characterize the physiological relevance of tetherin/BST-2 in those cells. To characterize the potential importance of tetherin/BST-2 to platelet function, we used tetherin/BST-2(-/-) murine platelets. In the mice, we found enhanced function and signaling downstream of a subset of membrane microdomain-expressing receptors, including the P2Y(12), TP thromboxane, thrombin, and GPVI receptors. Preliminary studies in humans have revealed that treatment with interferon-alpha (IFN-alpha), which upregulates platelet tetherin/BST-2 expression, also reduces adenosine diphosphate-stimulated platelet receptor function and reactivity. A more comprehensive understanding of how tetherin/BST-2 negatively regulates receptor function was provided in cell line experiments, where we focused on the therapeutically relevant P2Y(12) receptor (P2Y(12)R). Tetherin/BST-2 expression reduced both P2Y(12)R activation and trafficking, which was accompanied by reduced receptor lateral mobility specifically within membrane microdomains. In fluorescence lifetime imaging-Forster resonance energy transfer (FLIM-FRET)-based experiments, agonist stimulation reduced basal association between P2Y(12)R and tetherin/BST-2. Notably, the glycosylphosphatidylinositol (GPI) anchor of tetherin/BST-2 was required for both receptor interaction and observed functional effects. In summary, we established, for the first time, a fundamental role of the ubiquitously expressed protein tetherin/BST-2 in negatively regulating membrane microdomain-expressed platelet receptor function.

Automated summary

The protein tetherin/BST-2 plays a fundamental role in negatively regulating membrane microdomain-expressed platelet receptor function. Its expression reduces receptor activation and trafficking, enhancing the function of a subset of membrane microdomain-expressing receptors in platelets. This study provides insights into the physiological relevance of tetherin/BST-2 in platelet function and signaling.