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.
Highlights
Glycans from microbial pathogens are well known pathogen-associated molecular patterns that are recognized by the host immunity; little is known about whether and how mammalian self-glycans activate the host immune response, especially in the context of autoimmune disease
We previously demonstrated that loss of TREX1 C-terminus dysregulates the mammalian oligosaccharyltransferase (OST) activity leading to accumulation of free oligosaccharides in the cell, and that fOSs activate interferon-stimulated genes (ISGs) in macrophages[5]
We previously showed that fOS pools isolated from Trex1−/− cells are immunogenic when incubated with macrophages[5]
Summary
Glycans from microbial pathogens are well known pathogen-associated molecular patterns that are recognized by the host immunity; 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. Trex1−/− mice (loss of both DNase and glycan functions) develop severe early-onset systemic autoinflammatory disease with a short lifespan of 2–3 months[5,7]. We previously showed that TREX1-V235fs mutant mice express a DNase-active TREX1 truncation that lack glycan regulatory function and develop serologic autoimmunity by producing free glycans and autoantibodies against non-nuclear self-protein antigens[5,6]. We define structural requirements for bioactivity and immune profile of this self-derived disaccharide as well as its biogenesis and immune sensing pathway
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