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 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
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsSTRUCTURAL-ANALYSISALPHA-DYSTROGLYCANZEBRAFISH EMBRYOSFUKUTINBINDINGMUTATIONSGLYCANSMODELS2IMuscle, SkeletalBasement MembraneCell LineMyoblasts, SkeletalAnimalsZebrafishHumansMuscular DystrophiesMuscular Dystrophies, Limb-GirdleDisease Models, AnimalMuscular Dystrophy, AnimalGlycosyltransferasesPentosyltransferasesZebrafish ProteinsFibronectinsGlycosylationPhenotypeMutationMaleGene Knockout Techniques