Comparative glycoproteomics of stem cells identifies new players in ricin toxicity

Nature. 2017 Sep 28;549(7673):538-542. doi: 10.1038/nature24015. Epub 2017 Sep 20.

Abstract

Glycosylation, the covalent attachment of carbohydrate structures onto proteins, is the most abundant post-translational modification. Over 50% of human proteins are glycosylated, which alters their activities in diverse fundamental biological processes. Despite the importance of glycosylation in biology, the identification and functional validation of complex glycoproteins has remained largely unexplored. Here we develop a novel quantitative approach to identify intact glycopeptides from comparative proteomic data sets, allowing us not only to infer complex glycan structures but also to directly map them to sites within the associated proteins at the proteome scale. We apply this method to human and mouse embryonic stem cells to illuminate the stem cell glycoproteome. This analysis nearly doubles the number of experimentally confirmed glycoproteins, identifies previously unknown glycosylation sites and multiple glycosylated stemness factors, and uncovers evolutionarily conserved as well as species-specific glycoproteins in embryonic stem cells. The specificity of our method is confirmed using sister stem cells carrying repairable mutations in enzymes required for fucosylation, Fut9 and Slc35c1. Ablation of fucosylation confers resistance to the bioweapon ricin, and we discover proteins that carry a fucosylation-dependent sugar code for ricin toxicity. Mutations disrupting a subset of these proteins render cells ricin resistant, revealing new players that orchestrate ricin toxicity. Our comparative glycoproteomics platform, SugarQb, enables genome-wide insights into protein glycosylation and glycan modifications in complex biological systems.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryonic Stem Cells / chemistry*
  • Embryonic Stem Cells / drug effects*
  • Embryonic Stem Cells / enzymology
  • Embryonic Stem Cells / metabolism
  • Fucosyltransferases / genetics
  • Glycopeptides / analysis*
  • Glycopeptides / chemistry
  • Glycopeptides / metabolism
  • Glycoproteins / analysis*
  • Glycoproteins / chemistry
  • Glycoproteins / metabolism
  • Glycosylation
  • Humans
  • Membrane Transport Proteins / genetics
  • Mice
  • Monosaccharide Transport Proteins
  • Protein Processing, Post-Translational / genetics
  • Proteome / analysis*
  • Proteome / chemistry
  • Proteome / genetics
  • Proteome / metabolism
  • Proteomics*
  • Ricin / toxicity*

Substances

  • Glycopeptides
  • Glycoproteins
  • Membrane Transport Proteins
  • Monosaccharide Transport Proteins
  • Proteome
  • Slc35c1 protein, mouse
  • Ricin
  • Fucosyltransferases
  • fucosyltransferase 9, mouse