Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry

Science. 2013 Apr 26;340(6131):479-83. doi: 10.1126/science.1233675. Epub 2013 Mar 21.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Dystroglycans / metabolism*
  • Female
  • Glycosylation
  • Haploidy
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Infant
  • Lassa Fever / genetics*
  • Lassa Fever / virology
  • Lassa virus / physiology*
  • Male
  • Membrane Proteins / genetics*
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Pentosyltransferases
  • Proteome / metabolism*
  • Virus Internalization*
  • Walker-Warburg Syndrome / genetics*

Substances

  • Membrane Proteins
  • Proteome
  • Dystroglycans
  • Pentosyltransferases
  • RXYLT1 protein, human