Retrograde trafficking of β-dystroglycan from the plasma membrane to the nucleus

Abstract

β-Dystroglycan (β-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 β-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/β mediated nuclear import pathway has already been described for β-DG, the intracellular trafficking route by which β-DG reaches the nucleus is unknown. In this study, we demonstrated that β-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 β-DG from the ER membrane, making it accessible for importins and nuclear import. Finally, we show that phosphorylation of β-DG at Tyr890 is a key stimulus for β-DG nuclear translocation. Collectively our data describe the retrograde intracellular trafficking route that β-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.

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

“…A recent study in prostate cancer cells showed cell densitydependent γ-secretase and furin-mediated proteolysis of β-dystroglycan which could be stimulated by Notch, leading to nuclear targeting [111]. Another work uncovered the mechanism of retrograde trafficking of βdystroglycan from the plasma membrane to the nucleus [112]. In immortalized mouse C2C12 myoblasts, after being synthesized in the ER, α-Dg and β-Dg are transported from the ER to the Golgi apparatus and then to the plasma membrane, to form the DGC.…”

“…In immortalized mouse C2C12 myoblasts, after being synthesized in the ER, α-Dg and β-Dg are transported from the ER to the Golgi apparatus and then to the plasma membrane, to form the DGC. The phosphorylation on β-Dg on Tyr890 causes its endocytosis from the plasma membrane and retrograde intracellular trafficking to the ER and then to the nucleus, mediated by β-Dg interaction with the Sec61 translocon complex [112].…”

The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development

“…Although dystroglycans are usually detected in the cell membrane, a nuclear localization signaling (NLS) sequence has been identified in β-Dystroglycan (Lara-Chacón et al, 2010). There is also report that dystroglycans can be translocated to the nuclear membrane in C2C12 myoblast cell lines, playing an important role in maintaining the integrity of the nuclear envelope (Gracida-Jiménez et al, 2017;Velez Aguirela et al, 2018). Our results suggest that agrin regulates epicardial EMT through aggregation of dystroglycans.…”

The Molecular Basis and Biologic Significance of the β-Dystroglycan-Emerin Interaction

“…To reach the NE, β-DG undergoes retrograde trafficking from the cell surface to the nucleus, via the membranous endosome-endoplasmic reticulum (ER) route. Exit of β-DG from the ER membranous environment is facilitated by the Sec61 translocon complex [ 8 ] and nuclear translocation is completed through recognition of the β-DG nuclear localization signal by importins α2/β1 [ 9 ].…”

“…Within the nucleus β-DG forms a complex with the NE proteins emerin and lamins A/C and B1, to preserve nuclear structure and function [ 4 , 10 ] and probably to regulate gene expression [ 11 ]. It is possible that nuclear trafficking of β-DG connects functionally the plasma membrane with the NE, via an as yet undefined mechanism, thus allowing the cell to orchestrate nuclear activity in response to external stimuli [ 8 ]. A better characterization of the interaction between of β-DG and its NE interacting partners will help to decipher the molecular basis underlying its role in critical nuclear processes.…”