Identification of a post‐translational modification with ribitol‐phosphate and its defect in muscular dystrophy: Roles of ISPD, fukutin, and FKRP in α‐dystroglycan glycosylation

Abstract

Glycosylation is an essential post‐translational modification that underlies many biological processes and diseases. α‐dystroglycan (α‐DG) is a receptor for matrix and synaptic proteins that causes muscular dystrophy and lissencephaly upon its abnormal glycosylation (α‐dystroglycanopathies). Here we identify the glycan unit ribitol 5‐phosphate (Rbo5P), a phosphoric ester of pentose alcohol, in α‐DG. Rbo5P forms a tandem repeat and functions as a scaffold for the formation of the ligand‐binding moiety. We show that enzyme activities of three major α‐dystroglycanopathy‐causing proteins are involved in the synthesis of tandem Rbo5P. Isoprenoid synthase domain‐containing (ISPD) is cytidine diphosphate ribitol (CDP‐Rbo) synthase. Fukutin and fukutin‐related protein are sequentially acting Rbo5P transferases that use CDP‐Rbo. Consequently, Rbo5P glycosylation is defective in α‐dystroglycanopathy models. Supplementation of CDP‐Rbo to ISPD‐deficient cells restored α‐DG glycosylation. These findings establish the molecular basis of mammalian Rbo5P glycosylation and provide insight into pathogenesis and therapeutic strategies in α‐DG‐associated diseases.Support or Funding InformationJapan Society for the Promotion of Science 15H04352