title: Posttranslational modification of alpha-dystroglycan, the cellular receptor for arenaviruses, by the glycosyltransferase LARGE is critical for virus binding.
abstract: The receptor for lymphocytic choriomeningitis virus (LCMV), the human pathogenic Lassa fever virus (LFV), and clade C New World arenaviruses is alpha-dystroglycan (alpha-DG), a cell surface receptor for proteins of the extracellular matrix (ECM). Specific posttranslational modification of alpha-DG by the glycosyltransferase LARGE is critical for its function as an ECM receptor. In the present study, we show that LARGE-dependent modification is also crucial for alpha-DG's function as a cellular receptor for arenaviruses. Virus binding involves the mucin-type domain of alpha-DG and depends on modification by LARGE. A crucial role of the LARGE-dependent glycosylation of alpha-DG for virus binding is found for several isolates of LCMV, LFV, and the arenaviruses Mobala and Oliveros. Since the posttranslational modification by LARGE is crucial for alpha-DG recognition by both arenaviruses and the host-derived ligand laminin, it also influences competition between virus and laminin for alpha-DG. Hence, LARGE-dependent glycosylation of alpha-DG has important implications for the virus-host cell interaction and the pathogenesis of LFV in humans.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA. stefanku@scripps.edu
authors.forename: Stefan
authors.initials: S
authors.lastname: Kunz
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Rojek
authors.forename: Motoi
authors.initials: M
authors.lastname: Kanagawa
authors.forename: Christina F
authors.initials: CF
authors.lastname: Spiropoulou
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
mesh_terms: D000818:Animals; D001116:Arenaviridae / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D003433:Crosses, Genetic; D017931:DNA Primers; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism*; D049030:Dystroglycans / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D017931:DNA Primers; D014764:Viral Proteins; D049030:Dystroglycans; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; D012321:DNA-Directed RNA Polymerases