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

Charles S. Fermaintt, Kanae Sano, Zhida Liu, Nozomi Ishii, Junichi Seino, Nicole Dobbs, Tadashi Suzuki, Yang-Xin Fu, Mark A Lehrman, Ichiro Matsuo, Nan Yan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number2377
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Disaccharides
activity (biology)
Autoimmunity
Autoimmune Diseases
Polysaccharides
pathogens
Mannosidases
lysosomes
monosaccharides
lumens
Monosaccharides
immunity
Pathogens
Fractionation
Lysosomes
Bioactivity
antibodies
linkages
fractionation
Cytosol

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

A bioactive mammalian disaccharide associated with autoimmunity activates STING-TBK1-dependent immune response. / Fermaintt, Charles S.; Sano, Kanae; Liu, Zhida; Ishii, Nozomi; Seino, Junichi; Dobbs, Nicole; Suzuki, Tadashi; Fu, Yang-Xin; Lehrman, Mark A; Matsuo, Ichiro; Yan, Nan.

In: Nature communications, Vol. 10, No. 1, 2377, 01.12.2019.

Research output: Contribution to journalArticle

Fermaintt, Charles S. ; Sano, Kanae ; Liu, Zhida ; Ishii, Nozomi ; Seino, Junichi ; Dobbs, Nicole ; Suzuki, Tadashi ; Fu, Yang-Xin ; Lehrman, Mark A ; Matsuo, Ichiro ; Yan, Nan. / A bioactive mammalian disaccharide associated with autoimmunity activates STING-TBK1-dependent immune response. In: Nature communications. 2019 ; Vol. 10, No. 1.
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