Human UDP-galactose 4′-epimerase (GALE) is required for cell-surface glycome structure and function

Alex Broussard, Alyssa Florwick, Chelsea Desbiens, Nicole Nischan, Corrina Robertson, Ziqiang Guan, X. Jennifer J. Kohler, Lance Wells, Michael Boyce

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Glycan biosynthesis relies on nucleotide sugars (NSs), abundant metabolites that serve as monosaccharide donors for glycosyltransferases. In vivo, signal-dependent fluctuations in NS levels are required to maintain normal cell physiology and are dysregulated in disease. However, how mammalian cells regulateNSlevels and pathway flux remains largely uncharacterized. To address this knowledge gap, here we examined UDP-galactose 4-epimerase (GALE), which interconverts two pairs of essential NSs. Using immunoblotting, flow cytometry, and LC-MS-based glycolipid and glycan profiling, we found that CRISPR/Cas9-mediated GALE deletion in human cells triggers major imbalances in NSs and dramatic changes in glycolipids and glycoproteins, including a subset of integrins and the cellsurface death receptor FS-7-associated surface antigen. In particular, we observed substantial decreases in total sialic acid, galactose, and GalNAc levels in glycans. These changes also directly impacted cell signaling, as GALE-/- cells exhibited FS-7-associated surface antigen ligand-induced apoptosis. Our results reveal a role of GALE-mediated NS regulation in death receptor signaling and may have implications for the molecular etiology of illnesses characterized by NS imbalances, including galactosemia and metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)1225-1239
Number of pages15
JournalJournal of Biological Chemistry
Volume295
Issue number5
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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