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

摘要

Glycosylated a-dystroglycan (a-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 a-DG, but many genes mutated in WWS remain unknown. To identify modifiers of a-DG, we performed a haploid screen for Lassa virus entry, a hemorrhagic fever virus causing thousands of deaths annually that hijacks glycosylated a-DG to enter cells. In complementary screens, we profiled cells for absence of a-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 a-DG. Our findings accentuate the complexity of this posttranslational feature and point out genes defective in dystroglycanopathies.