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

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

Author information

1
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
2
Division of Molecular Science, Gunma University, Maebashi, 371-8510, Japan.
3
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
4
Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, 351-0198, Japan.
5
Department of Pharmacology, Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
6
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. nan.yan@utsouthwestern.edu.
7
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. nan.yan@utsouthwestern.edu.

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.

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