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

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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
    University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • 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, 2019. "A bioactive mammalian disaccharide associated with autoimmunity activates STING-TBK1-dependent immune response," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10319-5
    DOI: 10.1038/s41467-019-10319-5
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