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

• Published in: Nature communications Vol. 10; no. 1; p. 2377
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.05.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38; 38/77; 631/250/249/1313; 631/250/38; 631/45/221; Animals; Antibodies; Antibody response; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmunity - immunology; Biological activity; Cytosol; Disaccharides; Disaccharides - immunology; Disease Models, Animal; Endoplasmic Reticulum; Exodeoxyribonucleases - genetics; Fibroblasts; Fractionation; Glycan; High-performance liquid chromatography; Humanities and Social Sciences; Immune response; Immune system; Immunity; Immunity, Innate - immunology; Lipids; Liquid chromatography; Lysosomes; Mammals; Mannosidase; Membrane Proteins - immunology; Mice; Microorganisms; Monosaccharides; multidisciplinary; Oligosaccharides; Oligosaccharyltransferase; Pathogens; Pattern recognition; Phosphoproteins - genetics; Polysaccharides; Protein-Serine-Threonine Kinases - immunology; RAW 264.7 Cells; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10319-5

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. Mammalian glycans have a role in host immunity but little is known about how they activate the host response in the context of autoimmune diseases. Here, the authors identify Manβ1-4GlcNAc as a novel innate immune modulator associated with chronic autoimmune diseases.