FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy
journal contributionposted on 13.07.2021, 04:25 by AJ Wood, CH Lin, M Li, K Nishtala, S Alaei, F Rossello, C Sonntag, L Hersey, Lee MilesLee Miles, C Krisp, S Dudczig, AJ Fulcher, S Gibertini, PJ Conroy, A Siegel, M Mora, P Jusuf, NH Packer, PD Currie
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.
This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (PDC, NP: APP1127741, PDC: APP1136567, APP3151883). Australian Research Council Linkage (PDC: LP120100281) in collaboration with Sigma-Aldrich and LIEF Grant (LE150100110). The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. We acknowledge J Callaghan, I Harper, Monash Micro Imaging Facility, J Clark and A Costin, Monash Electron Microscopy Facility, L Kautto, Australian Proteomic Analysis Facility, W Moore, J Hilton and J Manneken, Aquacore core staff, Australian Regenerative Medicine Institute and Monash University Micromon sequencing facility for technical support. We also thank G Lynch and M Anderson for paper critiques.
Article NumberARTN 2951
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Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsSTRUCTURAL-ANALYSISALPHA-DYSTROGLYCANZEBRAFISH EMBRYOSFUKUTINBINDINGMUTATIONSGLYCANSMODELS2IMuscle, SkeletalBasement MembraneCell LineMyoblasts, SkeletalAnimalsZebrafishHumansMuscular DystrophiesMuscular Dystrophies, Limb-GirdleDisease Models, AnimalMuscular Dystrophy, AnimalGlycosyltransferasesPentosyltransferasesZebrafish ProteinsFibronectinsGlycosylationPhenotypeMutationMaleGene Knockout Techniques