RESUMO

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RESUMO

ß-Dystroglycan (ß-DG) is a plasma membrane protein that has ability to target to the nuclear envelope (NE) to maintain nuclear architecture. Nevertheless, mechanisms controlling ß-DG nuclear localization and the physiological consequences of a failure of trafficking are largely unknown. We show that ß-DG has a nuclear export pathway in myoblasts that depends on the recognition of a nuclear export signal located in its transmembrane domain, by CRM1. Remarkably, NES mutations forced ß-DG nuclear accumulation resulting in mislocalization and decreased levels of emerin and lamin B1 and disruption of various nuclear processes in which emerin (centrosome-nucleus linkage and ß-catenin transcriptional activity) and lamin B1 (cell cycle progression and nucleoli structure) are critically involved. In addition to nuclear export, the lifespan of nuclear ß-DG is restricted by its nuclear proteasomal degradation. Collectively our data show that control of nuclear ß-DG content by the combination of CRM1 nuclear export and nuclear proteasome pathways is physiologically relevant to preserve proper NE structure and activity.

Assuntos

Distroglicanas/metabolismo , Carioferinas/metabolismo , Laminina/metabolismo , Membrana Nuclear/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Linhagem Celular , Distroglicanas/genética , Carioferinas/genética , Laminina/genética , Camundongos , Membrana Nuclear/genética , Complexo de Endopeptidases do Proteassoma/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteína Exportina 1

RESUMO

ß-Dystroglycan (ß-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 ß-DG to target to, and conform specific protein assemblies at the plasma membrane (PM) and nuclear envelope (NE). Although a classical NLS and importin α/ß mediated nuclear import pathway has already been described for ß-DG, the intracellular trafficking route by which ß-DG reaches the nucleus is unknown. In this study, we demonstrated that ß-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 ß-DG from the ER membrane, making it accessible for importins and nuclear import. Finally, we show that phosphorylation of ß-DG at Tyr890 is a key stimulus for ß-DG nuclear translocation. Collectively our data describe the retrograde intracellular trafficking route that ß-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.