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 and Nan Yan ()
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Charles S. Fermaintt: University of Texas Southwestern Medical Center
Kanae Sano: Gunma University
Zhida Liu: University of Texas Southwestern Medical Center
Nozomi Ishii: Gunma University
Junichi Seino: Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research
Nicole Dobbs: University of Texas Southwestern Medical Center
Tadashi Suzuki: Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research
Yang-Xin Fu: University of Texas Southwestern Medical Center
Mark A. Lehrman: University of Texas Southwestern Medical Center
Ichiro Matsuo: Gunma University
Nan Yan: University of Texas Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10319-5

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