TY - JOUR
T1 - A bioactive mammalian disaccharide associated with autoimmunity activates STING-TBK1-dependent immune response
AU - Fermaintt, Charles S.
AU - Sano, Kanae
AU - Liu, Zhida
AU - Ishii, Nozomi
AU - Seino, Junichi
AU - Dobbs, Nicole
AU - Suzuki, Tadashi
AU - Fu, Yang Xin
AU - Lehrman, Mark A.
AU - Matsuo, Ichiro
AU - Yan, Nan
N1 - Funding Information:
We would like to thank Dr. Jennifer Kohler and members of the Yan lab for valuable discussions. This work was supported by the Lupus Research Alliance (N.Y.), the Clark family CRV Research Foundation (N.Y.), the NIH (AR067135 to N.Y., GM038545 to M.A.L.), the Welch Foundation (I-1831 to N.Y.) and NSF-GRFP fellowship (C.F.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-019-10319-5
DO - 10.1038/s41467-019-10319-5
M3 - Article
C2 - 31147550
AN - SCOPUS:85066499915
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2377
ER -