A bioactive mammalian disaccharide associated with autoimmunity activates STING-TBK1-dependent immune response

Nat Commun. 2019 May 30;10(1):2377. doi: 10.1038/s41467-019-10319-5.

Abstract

Glycans from microbial pathogens are well known pathogen-associated molecular patterns that are recognized by the host immunity; however, little is known about whether and how mammalian self-glycans activate the host immune response, especially in the context of autoimmune disease. Using biochemical fractionation and two-dimensional HPLC, we identify an abundant and bioactive free glycan, the Manβ1-4GlcNAc disaccharide in TREX1-associated autoimmune diseases. We report that both monosaccharide residues and the β1-4 linkage are critical for bioactivity of this disaccharide. We also show that Manβ1-4GlcNAc is produced by oligosaccharyltransferase hydrolysis of lipid-linked oligosaccharides in the ER lumen, followed by ENGase and mannosidase processing in the cytosol and lysosomes. Furthermore, synthetic Manβ1-4GlcNAc disaccharide stimulates a broad immune response in vitro, which is in part dependent on the STING-TBK1 pathway, and enhances antibody response in vivo. Together, our data identify Manβ1-4GlcNAc as a novel innate immune modulator associated with chronic autoimmune diseases.

Publication types

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

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • Autoimmunity / immunology*
  • Disaccharides / immunology*
  • Disease Models, Animal
  • Endoplasmic Reticulum
  • Exodeoxyribonucleases / genetics
  • Fibroblasts
  • Immunity, Innate / immunology*
  • Membrane Proteins / immunology*
  • Mice
  • Phosphoproteins / genetics
  • Protein-Serine-Threonine Kinases / immunology*
  • RAW 264.7 Cells

Substances

  • Disaccharides
  • Membrane Proteins
  • Phosphoproteins
  • Sting1 protein, mouse
  • 4-O-mannopyranosyl-2-acetamido-2-deoxyglucose
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1