Control of nuclear β-dystroglycan content is crucial for the maintenance of nuclear envelope integrity and function

Abstract

β-Dystroglycan (β-DG) is a plasma membrane protein that has ability to target to the nuclear envelope (NE) to maintain nuclear architecture. Nevertheless, mechanisms controlling β-DG nuclear localization and the physiological consequences of a failure of trafficking are largely unknown. We show that β-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 β-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 β-catenin transcriptional activity) and lamin B1 (cell cycle progression and nucleoli structure) are critically involved. In addition to nuclear export, the lifespan of nuclear β-DG is restricted by its nuclear proteasomal degradation. Collectively our data show that control of nuclear β-DG content by the combination of CRM1 nuclear export and nuclear proteasome pathways is physiologically relevant to preserve proper NE structure and activity.

Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability

“…In this study, we generated a C12C12 myoblasts-based model with no expression of DG (α-DG and β-DG) using CRISPR-Cas9 technology to provide insights into the nuclear function of β-DG. In earlier studies, we showed that β-DG is involved in maintaining the structure and function of the NE [ 20 , 21 ]; nevertheless, the specific mechanisms underlying its role in these nuclear processes remains to be determined. We isolated two DG-knockout clones (DG-KO1 and DG-KO2) that were generated from two different gRNAs.…”

“…We previously demonstrated that β-DG assembles with the nuclear envelope (NE) proteins emerin and lamins A/C and B1 to maintain nuclear architecture and function in myoblasts [ 20 ]. β-DG is subject to nucleocytoplasmic shuttling with an active exportin1/CRM1-mediated nuclear export pathway [ 21 ] that together with its nuclear import serves to tightly regulate the nuclear levels of β-DG, thereby allowing effective interactions with binding partners at the NE interface. However, the molecular basis underlying the role of β-DG on NE-associated functions is largely unknown.…”

Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity

“…The analysis of cell cycle was carried out on a BD LSRFortessa flow cytometer (BD Biosciences), using the ModFit LT software (Verity Software House). Cell proliferation was assessed by the 3‐(4,5‐dimethylthiazole‐2–5‐diphenyl tetrazolium bromide (MTT) assay, as reported previously (Velez‐Aguilera et al, ).…”

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

“…Considering the functional diversity of the NE it is likely that new NE-located proteins must still be identified. Our recent studies revealed that β-DG is a previously unrecognized NE component, which is likely to be involved in the maintenance of nuclear structure and function, probably by serving as a scaffold for the assembly of a NE protein complex composed of emerin and lamins A/C and B1 [ 4 , 10 ]. Thus, characterization of the molecular interaction of β-DG with NE proteins would help to decipher its function in the nucleus.…”

“…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 ].…”