Modifying Protein Modification: Alpha-dystroglycan (α-DG) is a cell-surface receptor that anchors the basal lamina to the sarcolemma by binding proteins containing laminin-G domains. This binding is essential for protecting muscle from contraction-induced injury, and defective binding is thought to cause a subclass of congenital muscular dystrophy (CMD) in humans. Mutations in six (putative) glycosyltransferase genes have been identified in patients with CMD, suggesting that glycosylation of α-DG may confer the ability to bind laminin. Despite extensive efforts for over 20 years, the actual laminin-binding moiety has remained unclear. Now, Yoshida-Moriguchi et al. (p. 88 ) have identified a phosphorylated O -mannosyl glycan on α-DG. This modification occurred in the Golgi via an unidentified kinase and was required for the maturation of α-DG into its laminin-binding form.

Among cells of the immune system, CD11c⁺ and DEC-205⁺ splenic dendritic cells primarily express the cellular receptor (α-dystroglycan [α-DG]) for lymphocytic choriomeningitis virus (LCMV). By selection, strains and variants of LCMV that bind α-DG with high affinity are associated with virus replication in the white pulp, show preferential replication in a majority of CD11c⁺ and DEC-205⁺ cells, cause immunosuppression, and establish a persistent infection. In contrast, viral strains and variants that bind with low affinity to α-DG are associated with viral replication in the red pulp, display minimal replication in CD11c⁺ and DEC-205⁺ cells, and generate a robust anti-LCMV cytotoxic T lymphocyte response that clears the virus infection. Differences in binding affinities can be mapped to a single amino acid change in the viral glycoprotein 1 ligand that binds to α-DG. These findings indicate that receptor–virus interaction on dendritic cells in vivo can be an essential step in the initiation of virus-induced immunosuppression and viral persistence.

Dystroglycan, which serves as a major extracellular matrix receptor in muscle and the central nervous system, requires extensive O-glycosylation to function. We identified a dystroglycan missense mutation (Thr192→Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment. A mouse model harboring this mutation recapitulates the immunohistochemical and neuromuscular abnormalities observed in the patient. In vitro and in vivo studies showed that the mutation impairs the receptor function of dystroglycan in skeletal muscle and brain by inhibiting the post-translational modification, mediated by the glycosyltransferase LARGE, of the phosphorylated O-mannosyl glycans on α-dystroglycan that is required for high-affinity binding to laminin.