FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

Abstract

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG’s glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.

Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies

“…Since our findings indicate that genes associated with ECM matrix receptor interaction and focal adhesions are dysregulated, we speculate that LGMDR9 mutations may also lead to a disruption in extracellular membrane binding. Interestingly, this is in line with recent data proposing that FKRP acts as a stabilizer of Fibronectin-Collagen 1 binding (Wood et al, 2021).…”

High degree of conservation of the enzymes synthesizing the laminin-binding glycoepitope of α-dystroglycan

“…Although this remains to be established, α-DG is the only O-mannosylated protein that has been extensively studied so far [80]; therefore, the possible existence of other proteins containing very similar M3 core structures cannot be ruled out. Recently, it has been reported that indeed FKRP directs sialylation of fibronectin at the muscle basement membrane, influencing the overall stability of sarcolemma in muscular dystrophy and therefore strongly suggesting the existence of multiple target/pathways, alternative to DG, affected by the 'M3' enzymes [81] The very high degree of conservation observed in Chordata strengthens the evidence that these 13 enzymes are important for muscle stability (figure 2). All considered, such remarkable conservation of the enzymatic cascade underlies the overall importance of α-DG carbohydrates for royalsocietypublishing.org/journal/rsob Open Biol.…”

“…Although this remains to be established, α-DG is the only O-mannosylated protein that has been extensively studied so far [ 80 ]; therefore, the possible existence of other proteins containing very similar M3 core structures cannot be ruled out. Recently, it has been reported that indeed FKRP directs sialylation of fibronectin at the muscle basement membrane, influencing the overall stability of sarcolemma in muscular dystrophy and therefore strongly suggesting the existence of multiple target/pathways, alternative to DG, affected by the ‘M3’ enzymes [ 81 ]…”

FKRP directed fibronectin glycosylation: A novel mechanism giving insights into muscular dystrophies?

“…[7] In a zebrafish model of fkrp gene mutation, recent work has uncovered a MBM failure resulting from aberrant sialylation of fibronectin. [8] Upon muscle development, fibronectin is a key ligand for the earliest F I G U R E 1 The Dystrophin-associated Glycoprotein Complex-Muscle Basement Membrane axis (DGC-MBM) and Dystroglycan protein structure. (A) Schematic representation of α-Dystroglycan biosynthesis and the DGC-MBM protein components and ligands in the muscle cell.…”