Xylose phosphatase activity of dystroglycan self-regulates its receptor function.

Dystroglycan (DG), a transmembrane receptor crucial for tissue development and pathogen entry, harbors a glycan composed of xylose and glucuronic acid called matriglycan. Loss of matriglycan or reduction in its length affects DG function, causing dystroglycanopathies. However, the mechanism underlying matriglycan extension is unknown. Here, we show that a Golgi xylose kinase facilitates initiation of matriglycan synthesis by transiently adding a phosphate to the xylose of matriglycan primer. Matriglycan extends when the phosphate is removed from xylose by the N-terminal domain of dystroglycan (DGN). DGN has the DXDXT/V motif found in haloacid dehalogenase (HAD) domains of hydrolases, conditional mutations in which reduce matriglycan length and cause disease in mice. Our work reveals an unexpected glycan phosphatase function of DG in regulating matriglycan extension on itself.