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 - 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.
UR - http://www.scopus.com/inward/record.url?scp=85066499915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066499915&partnerID=8YFLogxK
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 -