Retrograde Trafficking Of Beta-Dystroglycan From The Plasma Membrane To The Nucleus

beta-Dystroglycan (beta-DG) is a transmembrane protein with critical roles in cell adhesion, cytoskeleton remodeling and nuclear architecture. This functional diversity is attributed to the ability of beta-DG to target to, and conform specific protein assemblies at the plasma membrane (PM) and nuclear envelope (NE). Although a classical NLS and importin alpha/beta mediated nuclear import pathway has already been described for beta-DG, the intracellular trafficking route by which beta-DG reaches the nucleus is unknown. In this study, we demonstrated that beta-DG undergoes retrograde intracellular trafficking from the PM to the nucleus via the endosome-ER network. Furthermore, we provided evidence indicating that the translocon complex Sec61 mediates the release of beta-DG from the ER membrane, making it accessible for importins and nuclear import. Finally, we show that phosphorylation of beta-DG at Tyr(890) is a key stimulus for beta-DG nuclear translocation. Collectively our data describe the retrograde intracellular trafficking route that beta-DG follows from PM to the nucleus. This dual role for a cell adhesion receptor permits the cell to functionally connect the PM with the nucleus and represents to our knowledge the first example of a cell adhesion receptor exhibiting retrograde nuclear trafficking and having dual roles in PM and NE.