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

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.

MDA5 Is an Essential Sensor of a Pathogen-Associated Molecular Pattern Associated with Vitality That Is Necessary for Host Resistance against Aspergillus fumigatus

“…These data suggest that heat-sensitive fungal factors other than cell wall polysaccharides are responsible for driving the IFN response following respiratory A. fumigatus challenge. Consistent with this observation, individual polysaccharides commonly found in the A. fumigatus cell wall are not sufficient to induce an IFN response (73). Thus, other less-studied fungal traits that appear to require live fungi, are needed to induce a protective IFN response.…”

ER-directed TREX1 limits cGAS activation at micronuclei

“…Frameshift mutations that remove the C-terminus of TREX1 do not compromise exonuclease activity but are nevertheless associated with autoimmune diseases such as retinal vasculopathy with cerebral leukodystrophy and systemic lupus erythematosus (Lee-Kirsch et al, 2007;Richards et al, 2007;de Silva et al, 2007). Previous studies have proposed that the TREX1 C-terminus possesses a distinct, nuclease-independent function in the regulation of ER oligosaccharyltransferase complex activity (Fermaintt et al, 2019;Hasan et al, 2015;Kucej et al, 2017;Yan, 2017). Consequently, deleting the TREX1 C-terminus results in autoimmune disease and inflammation via the accumulation of free glycans (Fermaintt et al, 2019;Hasan et al, 2015).…”

“…Previous studies have proposed that the TREX1 C-terminus possesses a distinct, nuclease-independent function in the regulation of ER oligosaccharyltransferase complex activity (Fermaintt et al, 2019;Hasan et al, 2015;Kucej et al, 2017;Yan, 2017). Consequently, deleting the TREX1 C-terminus results in autoimmune disease and inflammation via the accumulation of free glycans (Fermaintt et al, 2019;Hasan et al, 2015).…”

The cGAS-STING Pathway in Hematopoiesis and Its Physiopathological Significance

“…HSPC maintenance is closely associated with the pathogenesis of autoimmune diseases. HSPCs confer protection to secondary infection, in a phenomenon termed "trained innate immunity" or "innate immune memory," which contributes to autoimmune diseases through exaggerating immune responses (114)(115)(116). Meanwhile, the myeloid progenitors released from the BM may infiltrate peripheral tissues and produce primed neutrophils in situ to exacerbate inflammatory responses within the affected tissues (117,118).…”