Deciphering the Glycosylome of Dystroglycanopathies Using Haploid Screens for Lassa Virus Entry

• Published in: Science (American Association for the Advancement of Science) Vol. 340; no. 6131; pp. 479 - 483
• Main Authors: Jae, Lucas T., Raaben, Matthijs, Riemersma, Moniek, van Beusekom, Ellen, Blomen, Vincent A., Velds, Arno, Kerkhoven, Ron. M., Carette, Jan E., Topaloglu, Haluk, Meinecke, Peter, Wessels, Marja W., Lefeber, Dirk J., Whelan, Sean P., van Bokhoven, Hans, Brummelkamp, Thijn R.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 26.04.2013; The American Association for the Advancement of Science
• Subjects: Amino Acid Sequence; Cell Line; Cell lines; Cellular; Cellular biology; congenital abnormalities; Disorders; Dystroglycans - metabolism; Female; Genes; Genetic mutation; Genetics; Glycoproteins; Glycosylation; Haploidy; Host-Pathogen Interactions - genetics; Humans; Infant; Integration host factors; Lassa Fever - genetics; Lassa Fever - virology; Lassa mammarenavirus; Lassa virus; Lassa virus - physiology; Male; Membrane Proteins - genetics; Molecular Sequence Data; Mutation; Mutations; Online; Pedigree; Proteome - metabolism; Screens; Sulfates; Viral infections; Virus Internalization; Viruses; Walker Warburg syndrome; Walker-Warburg Syndrome - genetics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1233675

Glycosylated α-dystroglycan (α-DG) serves as cellular entry receptor for multiple pathogens, and defects in its glycosylation cause hereditary Walker-Warburg syndrome (WWS). At least eight proteins are critical to glycosylate α-DG, but many genes mutated in WWS remain unknown. To identify modifiers of α-DG, we performed a haploid screen for Lassa virus entry, a hemorrhagic fever virus causing thousands of deaths annually that hijacks glycosylated α-DG to enter cells. In complementary screens, we profiled cells for absence of α-DG carbohydrate chains or biochemically related glycans. This revealed virus host factors and a suite of glycosylation units, including all known Walker-Warburg genes and five additional factors critical for the modification of α-DG. Our findings accentuate the complexity of this posttranslational feature and point out genes defective in dystroglycanopathies.